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    Clinical Trial Results:
    TIGER-1: A Randomized, Open-Label, Phase 2/3 Study of CO-1686 or Erlotinib as First-Line Treatment of Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Advanced/Metastatic Non-Small Cell Lung Cancer (NSCLC)

    Summary
    EudraCT number
    2014-000370-19
    Trial protocol
    DE   ES   FR   IT  
    Global end of trial date
    28 Jul 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Jun 2019
    First version publication date
    02 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CO-1686-022
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02186301
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Clovis Oncology UK Ltd
    Sponsor organisation address
    Sheraton House, Castle Park, Cambridge, United Kingdom, CB3 0AX
    Public contact
    Dr Lindsey Rolfe, Clovis Oncology UK Ltd, +44 1223370037, info@clovisoncology.com
    Scientific contact
    Dr Lindsey Rolfe, Clovis Oncology UK Ltd, +44 1223370037, info@clovisoncology.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
    28 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the antitumor efficacy of oral single-agent CO-1686 with that of erlotinib as measured by progression free survival (PFS), when administered as a first line targeted treatment to patients with EGFR-mutated, advanced/metastatic NSCLC
    Protection of trial subjects
    A data monitoring committee consisting of 3 of the clinical trial investigators and sponsor personnel met every 3 to 6 months to review and assess the safety and efficacy data, and provide recommendations regarding study continuation/discontinuation and protocol modifications.
    Background therapy
    -
    Evidence for comparator
    Erlotinib is approved in indication under study.
    Actual start date of recruitment
    01 Sep 2014
    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
    Hong Kong: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 20
    Country: Number of subjects enrolled
    Taiwan: 11
    Country: Number of subjects enrolled
    United States: 66
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    100
    EEA total number of subjects
    1
    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)
    50
    From 65 to 84 years
    47
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    100 subjects from 74 sites, in 7 countries randomized (1:1) to treatment with rociletinib or erlotinib. Original protocol had rociletinib starting dose of 625mg BID. In global Amendment 2, starting dose reduced to 500mg BID. Crossover to rociletinib was permitted, however, only 2 subjects did so. Safety data for these 2 subjects are reported.

    Pre-assignment
    Screening details
    Eligible patients were ≥ 18 years of age with advanced/metastatic NSCLC that had evidence of a tumor with activating EGFR and had undergone a biopsy or surgical resection of either primary or metastatic tumor tissue within 60 days of the first day of study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Rociletinib 625mg Tablets
    Arm description
    Starting dose of 625mg. Taken orally twice daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression.
    Arm type
    Experimental

    Investigational medicinal product name
    Rociletinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Starting dose of 625mg. Taken orally twice daily (continuous daily dosing).

    Arm title
    Rociletinib 500mg Tablets
    Arm description
    Starting dose of 500mg. Taken orally twice daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression.
    Arm type
    Experimental

    Investigational medicinal product name
    Rociletinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Starting dose of 500mg. Taken orally twice daily (continuous daily dosing).

    Arm title
    Erlotinib 150mg Tablets
    Arm description
    Starting dose of 150mg. Taken orally once daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression.
    Arm type
    Active comparator

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Tarceva
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Starting dose of 150mg. Taken orally once daily (continuous daily dosing).

    Number of subjects in period 1
    Rociletinib 625mg Tablets Rociletinib 500mg Tablets Erlotinib 150mg Tablets
    Started
    30
    20
    50
    Crossed Over to Rociletinib 500 mg BID
    0
    0
    1
    Crossed Over to Rociletinib 625 mg BID
    0
    0
    1
    Completed
    0
    0
    0
    Not completed
    30
    20
    50
         Study Terminated by Sponsor
    -
    1
    11
         Death
    -
    1
    -
         Protocol deviation
    2
    -
    -
         Missing
    -
    -
    2
         Physician decision
    -
    1
    1
         Unknown
    -
    -
    1
         Progressive Disease
    22
    7
    27
         Consent withdrawn by subject
    1
    5
    3
         Adverse Event
    5
    5
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rociletinib 625mg Tablets
    Reporting group description
    Starting dose of 625mg. Taken orally twice daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression.

    Reporting group title
    Rociletinib 500mg Tablets
    Reporting group description
    Starting dose of 500mg. Taken orally twice daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression.

    Reporting group title
    Erlotinib 150mg Tablets
    Reporting group description
    Starting dose of 150mg. Taken orally once daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression.

    Reporting group values
    Rociletinib 625mg Tablets Rociletinib 500mg Tablets Erlotinib 150mg Tablets Total
    Number of subjects
    30 20 50 100
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    13 9 28 50
        From 65-84 years
    16 10 21 47
        85 years and over
    1 1 1 3
    Age continuous
    Units: years
        median (full range (min-max))
    67 (41 to 85) 66 (44 to 86) 64 (39 to 88) -
    Gender categorical
    Units: Subjects
        Female
    18 17 32 67
        Male
    12 3 18 33
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    3 0 6 9
        Not Hispanic or Latino
    27 19 43 89
        Unknown or Not Reported
    0 1 1 2
    Race/Ethnicity, Customized 1
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    15 9 25 49
        Black or African American
    2 2 1 5
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        White
    12 9 21 42
        Other
    0 0 1 1
        Missing
    1 0 2 3
    Race/Ethnicity, Customized 2
    Units: Subjects
        White
    12 9 21 42
        Asian
    15 9 25 49
        Non-White, Non-Asian
    3 2 4 9
    Time Since Diagnosis of NSCLC
    Units: months
        arithmetic mean (standard deviation)
    5.3 ± 10.39 7.2 ± 14.12 8.2 ± 21.83 -

    End points

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    End points reporting groups
    Reporting group title
    Rociletinib 625mg Tablets
    Reporting group description
    Starting dose of 625mg. Taken orally twice daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression.

    Reporting group title
    Rociletinib 500mg Tablets
    Reporting group description
    Starting dose of 500mg. Taken orally twice daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression.

    Reporting group title
    Erlotinib 150mg Tablets
    Reporting group description
    Starting dose of 150mg. Taken orally once daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression.

    Primary: Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS)

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    End point title
    Progression Free Survival (PFS) According to RECIST Version 1.1 as Determined by Investigator Review (invPFS) [1]
    End point description
    Median InvPFS was calculated as 1+ the number of days from the date of randomization to documented radiographic progression as determined by the investigator, or death due to any cause, whichever occurs first. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. 1 patient in the Chemotherapy treatment group was not included in the analysis, due to discontinuation of study shortly after randomization and prior to first dose of study drug.
    End point type
    Primary
    End point timeframe
    Cycle 1 Day 1 to End of Treatment, up to approximately 35 months. This Time Frame includes the crossover period.
    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: Per EMA feedback, the statistical analyses section can not accommodate the end point results for this study. Therefore, for each end point, all statistical analyses details are provided in the End point values sections.
    End point values
    Rociletinib 625mg Tablets Rociletinib 500mg Tablets Erlotinib 150mg Tablets
    Number of subjects analysed
    30 [2]
    18 [3]
    50 [4]
    Units: PFS Days
    207
    274
    390
    Notes
    [2] - PFS Days - Confidence interval: level 95%, 2-sided, lower limit 112, upper limit 260
    [3] - PFS Days - Confidence interval: level 95%, 2-sided, lower limit 109, upper limit not available
    [4] - PFS Days - Confidence interval: level 95%, 2-sided, lower limit 282, upper limit 499
    No statistical analyses for this end point

    Secondary: Percentage of Patients With Confirmed Response

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    End point title
    Percentage of Patients With Confirmed Response
    End point description
    Percentage of patients with a best overall confirmed response of partial response (PR) or complete response (CR) recorded from the start of the treatment until disease progression or recurrence. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions, defined by and assessed as: Complete Response (CR), is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. Partial Response (PR),at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Overall Response (OR),is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment was dependent on the achievement of both measurement and confirmation criteria.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 to End of Treatment, up to approximately 35 months. This Time Frame includes the crossover period.
    End point values
    Rociletinib 625mg Tablets Rociletinib 500mg Tablets Erlotinib 150mg Tablets
    Number of subjects analysed
    30 [5]
    20 [6]
    50 [7]
    Units: Percentage of patients
    40
    25
    78
    Notes
    [5] - Percentage of Patients - Confidence interval: level 95%, 2-sided, lower limit 22.7, upper limit 59.4
    [6] - Percentage of Patients - Confidence interval: level 95%, 2-sided, lower limit 8.7, upper limit 49.1
    [7] - Percentage of Patients - Confidence interval: level 95%, 2-sided, lower limit 64.0, upper limit 88.5
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) According to RECIST Version 1.1 as Determined by Investigator Assessment

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    End point title
    Duration of Response (DOR) According to RECIST Version 1.1 as Determined by Investigator Assessment
    End point description
    Median Duration of Response in patients with confirmed response per investigator. The DOR for complete response (CR) and partial response (PR) was measured from the date that any of these best responses is first recorded until the first date that progressive disease (PD) is objectively documented. For patients who continue treatment post-progression, the first date of progression was used for the analysis.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 to End of Treatment, up to approximately 35 months
    End point values
    Rociletinib 625mg Tablets Rociletinib 500mg Tablets Erlotinib 150mg Tablets
    Number of subjects analysed
    12 [8]
    5 [9]
    39 [10]
    Units: DOR Days
    195
    225
    335
    Notes
    [8] - DOR Days - Confidence interval: level 95%, 2-sided, lower limit 143, upper limit 617
    [9] - DOR Days - Confidence interval: level 95%, 2-sided, lower limit 113, upper limit not available
    [10] - DOR Days - Confidence interval: level 95%, 2-sided, lower limit 282, upper limit 480
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from the date of first dose of study drug and until 28 days after last dose of study drug.
    Adverse event reporting additional description
    If a subject experiences the same preferred term (system organ class) multiple times, then the subject will be counted only once for that preferred term (system organ class). Treatment Arm/Groups for the 2 subjects who crossed over to Rociletinib dose groups (1 per group) from Erlotinib are included. However, only 1 crossover subject reported AEs.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Rociletinib 625mg Tablets
    Reporting group description
    Starting dose of 625mg. Taken orally twice daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression.

    Reporting group title
    Rociletinib 500mg Tablets
    Reporting group description
    Starting dose of 500mg. Taken orally twice daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression.

    Reporting group title
    Erlotinib 150mg Tablets
    Reporting group description
    Starting dose of 150mg. Taken orally once daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression.

    Reporting group title
    Crossover From Erlotinib 150mg to Rociletinib 500mg
    Reporting group description
    Patients initially randomized to erlotinib were eligible to participate in an optional crossover phase to receive Rociletinib. Starting dose of 500mg Rociletinib. Taken orally twice daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression.

    Reporting group title
    Crossover From Erlotinib 150mg to Rociletinib 625mg
    Reporting group description
    Patients initially randomized to erlotinib were eligible to participate in an optional crossover phase to receive Rociletinib. Starting dose of 625mg Rociletinib. Taken orally twice daily (continuous 28 day treatment cycle). Treatment duration until radiographically confirmed disease progression.

    Serious adverse events
    Rociletinib 625mg Tablets Rociletinib 500mg Tablets Erlotinib 150mg Tablets Crossover From Erlotinib 150mg to Rociletinib 500mg Crossover From Erlotinib 150mg to Rociletinib 625mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 30 (50.00%)
    10 / 19 (52.63%)
    7 / 50 (14.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         number of deaths (all causes)
    1
    3
    2
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site haematoma
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Cardiac murmur
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Torsade de pointes
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paranasal cyst
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 19 (10.53%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 19 (10.53%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute cholangtis, Acute cholecystitis and acute pancreatitis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polydipsia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Enterocolitis infectious
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 19 (10.53%)
    2 / 50 (4.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Rociletinib 625mg Tablets Rociletinib 500mg Tablets Erlotinib 150mg Tablets Crossover From Erlotinib 150mg to Rociletinib 500mg Crossover From Erlotinib 150mg to Rociletinib 625mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 30 (100.00%)
    19 / 19 (100.00%)
    50 / 50 (100.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    1
    1
    4
    0
    3
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 19 (5.26%)
    2 / 50 (4.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    1
    2
    0
    0
    Catheter site haematoma
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Catheter site inflammation
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Catheter site pain
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Chest discomfort
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 19 (5.26%)
    2 / 50 (4.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    2
    0
    0
    Chest pain
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 19 (0.00%)
    4 / 50 (8.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    4
    0
    0
    Chills
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 19 (0.00%)
    2 / 50 (4.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    Fatigue
         subjects affected / exposed
    9 / 30 (30.00%)
    6 / 19 (31.58%)
    12 / 50 (24.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    11
    7
    16
    0
    3
    Malaise
         subjects affected / exposed
    3 / 30 (10.00%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    5 / 50 (10.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    5
    0
    0
    Oedema peripheral
         subjects affected / exposed
    4 / 30 (13.33%)
    2 / 19 (10.53%)
    5 / 50 (10.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    3
    5
    0
    0
    Pain
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    3 / 50 (6.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    Pyrexia
         subjects affected / exposed
    3 / 30 (10.00%)
    0 / 19 (0.00%)
    2 / 50 (4.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    2
    0
    0
    Oedema
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 30 (13.33%)
    1 / 19 (5.26%)
    7 / 50 (14.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    1
    7
    0
    0
    Depression
         subjects affected / exposed
    6 / 30 (20.00%)
    1 / 19 (5.26%)
    4 / 50 (8.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    7
    1
    4
    0
    0
    Insomnia
         subjects affected / exposed
    3 / 30 (10.00%)
    5 / 19 (26.32%)
    7 / 50 (14.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    5
    9
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    4 / 50 (8.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    6
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    5 / 50 (10.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    7
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    5 / 50 (10.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    3
    14
    0
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    7 / 30 (23.33%)
    2 / 19 (10.53%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    16
    2
    1
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    0
    0
    0
    Platelet count decreased
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Weight decreased
         subjects affected / exposed
    5 / 30 (16.67%)
    3 / 19 (15.79%)
    4 / 50 (8.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    10
    6
    8
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    2
    0
    0
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    3 / 50 (6.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    3
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    Cough
         subjects affected / exposed
    6 / 30 (20.00%)
    5 / 19 (26.32%)
    13 / 50 (26.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    6
    5
    14
    0
    2
    Dysphonia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    3 / 50 (6.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Dyspnoea
         subjects affected / exposed
    7 / 30 (23.33%)
    4 / 19 (21.05%)
    7 / 50 (14.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    8
    4
    8
    0
    2
    Dyspnoea exertional
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 19 (5.26%)
    2 / 50 (4.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    2
    0
    0
    Hypoxia
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 19 (0.00%)
    4 / 50 (8.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    4
    0
    0
    Pleural effusion
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 19 (10.53%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    3
    1
    0
    0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 19 (10.53%)
    6 / 50 (12.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    1
    2
    7
    0
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    3 / 50 (6.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    3
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Anaemia
         subjects affected / exposed
    2 / 30 (6.67%)
    6 / 19 (31.58%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    2
    9
    1
    0
    1
    Leukopenia
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Lymphopenia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    2
    Neutropenia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    1
    0
    0
    0
    2
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Dizziness
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 19 (15.79%)
    9 / 50 (18.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    3
    11
    0
    0
    Headache
         subjects affected / exposed
    5 / 30 (16.67%)
    2 / 19 (10.53%)
    3 / 50 (6.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    8
    2
    3
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    2
    1
    0
    0
    1
    Syncope
         subjects affected / exposed
    3 / 30 (10.00%)
    0 / 19 (0.00%)
    2 / 50 (4.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    3
    0
    0
    Dysgeusia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    1
    0
    2
    0
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 19 (5.26%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    1
    1
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    7 / 50 (14.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    8
    0
    0
    Vision blurred
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Ear and labyrinth disorders
    Ear congestion
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 30 (10.00%)
    3 / 19 (15.79%)
    4 / 50 (8.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    4
    6
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 19 (15.79%)
    2 / 50 (4.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    6
    3
    0
    0
    Constipation
         subjects affected / exposed
    6 / 30 (20.00%)
    3 / 19 (15.79%)
    2 / 50 (4.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    6
    3
    3
    0
    2
    Diarrhoea
         subjects affected / exposed
    15 / 30 (50.00%)
    7 / 19 (36.84%)
    33 / 50 (66.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    26
    12
    48
    0
    0
    Dry mouth
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    3 / 50 (6.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    3
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 30 (3.33%)
    4 / 19 (21.05%)
    3 / 50 (6.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    5
    4
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 30 (10.00%)
    2 / 19 (10.53%)
    6 / 50 (12.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    3
    2
    6
    0
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    8 / 30 (26.67%)
    10 / 19 (52.63%)
    7 / 50 (14.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    11
    13
    8
    0
    1
    Stomatitis
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 19 (0.00%)
    9 / 50 (18.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    12
    0
    0
    Vomiting
         subjects affected / exposed
    6 / 30 (20.00%)
    5 / 19 (26.32%)
    4 / 50 (8.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    7
    5
    5
    0
    1
    Abdominal discomfort
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Odynophagia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Cholelithiasis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    8 / 50 (16.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    9
    0
    0
    Dermatitis acneiform
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    18 / 50 (36.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    37
    0
    0
    Dry skin
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    9 / 50 (18.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    10
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Pruritus
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 19 (0.00%)
    6 / 50 (12.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    6
    0
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Rash
         subjects affected / exposed
    3 / 30 (10.00%)
    4 / 19 (21.05%)
    26 / 50 (52.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    5
    42
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Skin fissures
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    4 / 50 (8.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    5
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 19 (5.26%)
    4 / 50 (8.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    5
    2
    5
    0
    0
    Back pain
         subjects affected / exposed
    4 / 30 (13.33%)
    0 / 19 (0.00%)
    7 / 50 (14.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    7
    0
    10
    0
    0
    Muscle spasms
         subjects affected / exposed
    5 / 30 (16.67%)
    5 / 19 (26.32%)
    3 / 50 (6.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    6
    9
    3
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 19 (0.00%)
    3 / 50 (6.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    3
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 19 (10.53%)
    5 / 50 (10.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    2
    5
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 19 (10.53%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    3
    1
    0
    0
    Pain in extremity
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    6 / 50 (12.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    6
    0
    0
    Endocrine disorders
    Tachycardia
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 19 (15.79%)
    2 / 50 (4.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    3
    2
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    5 / 30 (16.67%)
    5 / 19 (26.32%)
    9 / 50 (18.00%)
    0 / 1 (0.00%)
    1 / 1 (100.00%)
         occurrences all number
    5
    5
    12
    0
    1
    Dehydration
         subjects affected / exposed
    3 / 30 (10.00%)
    3 / 19 (15.79%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    3
    1
    0
    0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    15 / 30 (50.00%)
    10 / 19 (52.63%)
    2 / 50 (4.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    28
    23
    2
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    1 / 50 (2.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    2 / 50 (4.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    3
    0
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 19 (10.53%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Polydipsia
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 19 (15.79%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    4
    0
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Candida infection
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 19 (0.00%)
    3 / 50 (6.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    Infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 19 (10.53%)
    3 / 50 (6.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    2
    3
    0
    0
    Oral candidiasis
         subjects affected / exposed
    3 / 30 (10.00%)
    0 / 19 (0.00%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Paronychia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    10 / 50 (20.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    12
    0
    0
    Pneumonia
         subjects affected / exposed
    3 / 30 (10.00%)
    2 / 19 (10.53%)
    2 / 50 (4.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    2
    2
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 19 (0.00%)
    8 / 50 (16.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    1
    0
    12
    0
    0
    Urinary tract infection
         subjects affected / exposed
    4 / 30 (13.33%)
    0 / 19 (0.00%)
    6 / 50 (12.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    4
    0
    6
    0
    0
    Vaginal infection
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 19 (5.26%)
    0 / 50 (0.00%)
    0 / 1 (0.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jan 2015
    In global Amendment 1 (Version 2.0), a Phase 3 part was added and randomization of an additional 1,000 patients was allowed.
    23 Apr 2015
    In global Amendment 2 (Version 3.0), the dose of rociletinib was decreased from 625 mg BID to 500 mg BID. Emerging data from the first-in-human study showed that whilst there was no difference in efficacy, 500 mg BID provided better tolerability than 625 mg BID. For Amendment 2, there were also country-specific addenda in Germany (Version 3.1, 23 July 2015 and Version 3.2, 12 August 2015), to specify closer monitoring of electrocardiogram (ECG) parameters and to clarify patients required to undergo an End-of-Treatment scan, and South Korea (Version 3.1, 23 April 2015) specifying that rociletinib may cause hyperglycemia in some patients and to provide monitoring guidelines.
    22 Aug 2016
    In a global Amendment 3 (Version 4.0), details regarding the discontinuation of clinical development of rociletinib were provided; an extension phase was added allowing patients to continue on study if they were deriving clinical benefit and removing the option for patients to crossover to rociletinib following radiographic progression on erlotinib. In addition, the availability of N-acetyltransferase 2 testing for patients, an indirect indicator of the likelihood of developing hyperglycemia and QT interval corrected for heart rate (QTc) prolongation, was introduced.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    16 Dec 2015
    On 16 December 2015, investigators were notified of early enrollment closure based on the de-prioritization of the rociletinib clinical development program. No new patients were permitted to consent effective 24 December 2015 or were randomized effective 05 February 2016. Due to early closure, 100 patients were included in Phase 2 and no patients were enrolled in Phase 3.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    For two end points, Progression Free Survival and Duration of Response, the Statistical Analysis upper Confidence Limits are not available because they could not be calculated.
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