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    Clinical Trial Results:
    PHASE 3, RANDOMIZED, OPEN LABEL STUDY OF THE EFFICACY AND SAFETY OF PF-02341066 VERSUS STANDARD OF CARE CHEMOTHERAPY (PEMETREXED OR DOCETAXEL) IN PATIENTS WITH ADVANCED NON SMALL CELL LUNG CANCER (NSCLC) HARBORING A TRANSLOCATION OR INVERSION EVENT INVOLVING THE ANAPLASTIC LYMPHOMA KINASE (ALK) GENE LOCUS

    Summary
    EudraCT number
    2009-012595-27
    Trial protocol
    GB   NL   DE   PL   ES   HU   FR   GR   IT   IE   BG   SE  
    Global end of trial date
    05 Jan 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Nov 2016
    First version publication date
    19 Nov 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A8081007
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00932893
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 East 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.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
    14 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Mar 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jan 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that crizotinib was superior to standard of care chemotherapy, pemetrexed or docetaxel, in prolonging Progression Free Survival (PFS) in patients with advanced Non-small cell lung cancer (NSCLC) whose tumors harbor a translocation or inversion event involving the anaplastic lymphoma kinase (ALK) gene locus and who had received only 1 prior chemotherapy regimen for advanced NSCLC and this regimen must have been platinum-based.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed; in particular, those affording greater protection to the safety of study participants.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    18 Sep 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    66 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 46
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Brazil: 7
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    China: 23
    Country: Number of subjects enrolled
    France: 18
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Hong Kong: 3
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Ireland: 8
    Country: Number of subjects enrolled
    Italy: 53
    Country: Number of subjects enrolled
    Japan: 68
    Country: Number of subjects enrolled
    Korea, Republic of: 50
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Russian Federation: 4
    Worldwide total number of subjects
    347
    EEA total number of subjects
    131
    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)
    297
    From 65 to 84 years
    49
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    histologically or cytologically proven diagnosis of locally advanced or metastatic nonsmall cell lung cancer; positive for translocation or inversion in ALK gene locus; progressive disease after only 1 prior platinum based chemotherapy regimen.

    Pre-assignment
    Screening details
    Screening procedures were completed up to 28 days before randomization to study treatment. Post-screening, 4 participants discontinued the study and did not go on to receive the first dose of study treatment. A total of 343 participants were randomized and received at least one dose of study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Crizotinib
    Arm description
    Crizotinib (PF-02341066) 250 mg (administered as two 100-mg tablets and one 50-mg tablet) orally twice daily continuously in 21-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred.
    Arm type
    Experimental

    Investigational medicinal product name
    Crizotinib
    Investigational medicinal product code
    PF-02341066
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    250 mg tablets twice a day

    Arm title
    Chemotherapy
    Arm description
    Pemetrexed 500 mg per square meter (mg/m^2) intravenous infusion over 10 minutes or docetaxel 75 mg/m^2 intravenous infusion over 1 hour on Day 1 of 21-day cycle, as per investigator discretion. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred.
    Arm type
    Active comparator

    Investigational medicinal product name
    Pemetrexed or Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intramuscular and intravenous use
    Dosage and administration details
    500mg/m2 of pemetrexed or 75mg/m2 of docetaxel

    Number of subjects in period 1
    Crizotinib Chemotherapy
    Started
    173
    174
    Randomized and not treated
    1 [1]
    3 [2]
    Randomized and treated
    172
    171
    Completed
    40
    4
    Not completed
    133
    170
         Adverse event, serious fatal
    115
    24
         Unspecified
    5
    144
         Consent withdrawn by subject
    5
    2
         Lost to follow-up
    8
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 173 subjects were enrolled however 1 subject withdrew prior to treatment and was never treated.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 174 subjects were enrolled however 3 subjects withdrew prior to treatment and were never treated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Crizotinib
    Reporting group description
    Crizotinib (PF-02341066) 250 mg (administered as two 100-mg tablets and one 50-mg tablet) orally twice daily continuously in 21-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred.

    Reporting group title
    Chemotherapy
    Reporting group description
    Pemetrexed 500 mg per square meter (mg/m^2) intravenous infusion over 10 minutes or docetaxel 75 mg/m^2 intravenous infusion over 1 hour on Day 1 of 21-day cycle, as per investigator discretion. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred.

    Reporting group values
    Crizotinib Chemotherapy Total
    Number of subjects
    173 174 347
    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)
    146 151 297
        From 65-84 years
    27 22 49
        85 years and over
    0 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    50.3 ± 13.1 49.8 ± 13 -
    Gender, Male/Female
    Units: participants
        Female
    98 95 193
        Male
    75 79 154

    End points

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    End points reporting groups
    Reporting group title
    Crizotinib
    Reporting group description
    Crizotinib (PF-02341066) 250 mg (administered as two 100-mg tablets and one 50-mg tablet) orally twice daily continuously in 21-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred.

    Reporting group title
    Chemotherapy
    Reporting group description
    Pemetrexed 500 mg per square meter (mg/m^2) intravenous infusion over 10 minutes or docetaxel 75 mg/m^2 intravenous infusion over 1 hour on Day 1 of 21-day cycle, as per investigator discretion. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred.

    Primary: Progression-Free Survival (PFS)

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    End point title
    Progression-Free Survival (PFS)
    End point description
    PFS: Time in months from randomization to first documentation of objective disease progression as determined by independent radiology review or to death due to any cause, whichever occurred first. PFS was calculated as (first event date minus the date of randomization plus 1) divided by 30.4. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria version 1.1 (RECIST v1.1), as at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
    End point type
    Primary
    End point timeframe
    Randomization until progressive disease (PD) or initiation of antitumor therapy in the absence of PD or death, assessed every 6 weeks (up to 112 weeks)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    173
    174
    Units: months
        median (confidence interval 95%)
    7.7 (6 to 8.8)
    3 (2.6 to 4.3)
    Statistical analysis title
    Progression Free Survival
    Statistical analysis description
    P-value was obtained from 1-sided log-rank test stratified by Eastern Cooperative Oncology Group performance status (ECOG PS) score, brain metastases, and prior epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) treatment. The hazard ratio and corresponding 95% confidence interval (CI) from the stratified Cox Proportional Hazards model were also presented.
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001 [1]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.487
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.371
         upper limit
    0.638
    Notes
    [1] - To control family-wise Type 1 error, a step-down procedure was applied in following order: PFS, objective response rate (ORR), overall survival (OS), and disease control rate (DCR). Statistical significance: 1-sided at alpha=0.025.

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS: Time in months from randomization to date of death due to any cause. OS was calculated as (the death date minus the date of randomization plus 1) divided by 30.4.
    End point type
    Secondary
    End point timeframe
    Randomization until death (up to 4.5 years)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    173
    174
    Units: months
        median (confidence interval 95%)
    21.7 (18.9 to 30.5)
    21.9 (16.8 to 26)
    Statistical analysis title
    Overall Survival
    Statistical analysis description
    P-value was obtained from 1-sided log-rank test stratified by ECOG PS score, brain metastases, and prior EGFR TKI treatment. The hazard ratio and corresponding 95% CI from the stratified Cox proportional hazards model were also presented.
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.1145 [2]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.854
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.661
         upper limit
    1.104
    Notes
    [2] - Statistical significance: 1-sided at alpha=0.025

    Secondary: Overall Survival Probability at Months 6 and 12

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    End point title
    Overall Survival Probability at Months 6 and 12
    End point description
    Overall survival probability at Month 6 and 12 was defined as the probability of survival at 6 and 12 months respectively, after the randomization of study treatment. The survival probability was estimated using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Month 6, 12
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    173
    174
    Units: percentage
    number (confidence interval 95%)
        Month 6
    86.6 (80.5 to 90.9)
    83.8 (77.4 to 88.5)
        Month 12
    70.4 (62.9 to 76.7)
    66.7 (59.1 to 73.2)
    No statistical analyses for this end point

    Secondary: Objective Response rate (ORR)

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    End point title
    Objective Response rate (ORR)
    End point description
    Percentage of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to RECIST v1.1. CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 millimeter [mm] short axis). PR: at least 30 percent (%) decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Objective response is based on independent radiology review.
    End point type
    Secondary
    End point timeframe
    Randomization until PD or initiation of antitumor therapy in the absence of PD or death, assessed every 6 weeks (up to 112 weeks)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    173
    174
    Units: percentage of participants
        number (confidence interval 95%)
    65.3 (57.7 to 72.4)
    19.5 (13.9 to 26.2)
    Statistical analysis title
    Participants % with OR
    Statistical analysis description
    P-value was obtained from Cochran-Mantel-Haenszel (CMH) test stratified by ECOG PS, brain metastases, and prior EGFR TKI treatment. The risk ratio and corresponding 95% CI from the stratified CMH test were also reported.
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk ratio (RR)
    Point estimate
    3.394
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.463
         upper limit
    4.676
    Notes
    [3] - Statistical significance: 2-sided at alpha=0.025.

    Secondary: Percentage of Participants With Disease Control at Week 6

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    End point title
    Percentage of Participants With Disease Control at Week 6
    End point description
    Disease control: participants with CR, PR, or stable disease (SD) according to RECIST v1.1. CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis). PR: at least 30 % decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. Disease control is based on independent radiology review.
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    173
    174
    Units: percentage of participants
        number (confidence interval 95%)
    81.5 (74.9 to 87)
    55.2 (47.5 to 62.7)
    Statistical analysis title
    Participants % With Disease Control at Week 6
    Statistical analysis description
    P-value was obtained from CMH test stratified by ECOG PS, brain metastases, and prior EGFR TKI treatment. The risk ratio and corresponding 95% CI from the stratified CMH test were also reported.
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    < 0.0001 [4]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.502
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.297
         upper limit
    1.741
    Notes
    [4] - Statistical significance: 2-sided at alpha=0.0004.

    Secondary: Percentage of Participants With Disease Control at Week 12

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    End point title
    Percentage of Participants With Disease Control at Week 12
    End point description
    Disease control: participants with CR, PR, or SD according to RECIST v1.1. CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis). PR: at least 30 % decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase (including an absolute increase of at least 5 mm) in the sum of diameters of target lesions, taking as reference the smallest sum on study and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    173
    174
    Units: percentage of participants
        number (confidence interval 95%)
    64.2 (56.5 to 71.3)
    38.5 (31.2 to 46.2)
    Statistical analysis title
    Participants % With Disease Control at Week 12
    Statistical analysis description
    P-value was obtained from CMH test stratified by ECOG PS, brain metastases, and prior EGFR TKI treatment. The risk ratio and corresponding 95% CI from the stratified CMH test were also reported.
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    347
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001 [5]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk ratio (RR)
    Point estimate
    1.697
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.368
         upper limit
    2.103
    Notes
    [5] - Statistical significance: 2-sided at alpha=0.0004.

    Secondary: Duration of Response (DR)

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    End point title
    Duration of Response (DR)
    End point description
    Time in weeks from the first documentation of objective tumor response to objective tumor progression or death due to any cause. Duration of tumor response was calculated as (the date of the first documentation of objective tumor progression or death due to any cause minus the date of the first CR or PR that was subsequently confirmed plus 1) divided by 7.02. DR was calculated for the subgroup of participants with a confirmed objective tumor response.
    End point type
    Secondary
    End point timeframe
    Randomization until PD or initiation of antitumor therapy in the absence of PD or death, assessed every 6 weeks (up to 112 weeks)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    113
    34
    Units: weeks
        median (confidence interval 95%)
    32.1 (26.4 to 42.3)
    24.4 (15 to 36)
    No statistical analyses for this end point

    Secondary: Time to Tumor Response (TTR)

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    End point title
    Time to Tumor Response (TTR)
    End point description
    Time from date of randomization to first documentation of objective tumor response. TTR was calculated for the subgroup of participants with objective tumor response. Objective tumor response was defined as CR or PR according to RECIST v1.1. CR: disappearance of all target and non-target lesions and normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis). PR: at least 30 % decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits.
    End point type
    Secondary
    End point timeframe
    Randomization until PD or initiation of antitumor therapy in the absence of PD or death, assessed every 6 weeks (up to 112 weeks)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    113
    34
    Units: weeks
        median (full range (min-max))
    6.3 (4.4 to 48.4)
    12.6 (5 to 37.1)
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Crizotinib

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    End point title
    Plasma Concentration of Crizotinib [6]
    End point description
    Only participants receiving crizotinib were to be analyzed for this outcome measure as per planned analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Cycle 1 Day 1 and Cycle Day 15, and Day 1 of Cycle 1, 2, 3, 5
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants receiving crizotinib were to be analyzed for this outcome measure as per planned analysis.
    End point values
    Crizotinib
    Number of subjects analysed
    152
    Units: nanogram per milliliter (ng/mL)
    geometric mean (standard deviation)
        Cycle 1 Day 1 (n=15)
    0 ± 0
        Cycle 1 Day 15 (n=92)
    298 ± 148
        Cycle 2 Day 1 (n=62)
    293 ± 154
        Cycle 3 Day 1 (n=61)
    306 ± 135
        Cycle 5 Day 1 (n=47)
    291 ± 156
    No statistical analyses for this end point

    Secondary: Number of Participants With Categorical Maximum QTcF for Crizotinib

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    End point title
    Number of Participants With Categorical Maximum QTcF for Crizotinib [7]
    End point description
    QT interval corrected using Fridericia’s formula (QTcF): QT interval (time corresponding to the beginning of depolarization to re-polarization of the ventricles) divided by cube root of RR interval. Maximum QTcF was categorized as less than (<) 450 milliseconds (msec), 450 msec to <480 msec, 480 msec to <500 msec, and more than or equal to (>=) 500 msec. A participant is reported only once under the maximum QTcF interval observed at any of the time-points. Only participants receiving crizotinib were to be analyzed for this outcome measure as per planned analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 of Cycle 1, 2 to 6 hours post-dose on Day 1 of Cycle 1, 2
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only participants receiving crizotinib were to be analyzed for this outcome measure as per planned analysis.
    End point values
    Crizotinib
    Number of subjects analysed
    155
    Units: participants
        <450 msec
    137
        450 msec to <480 msec
    9
        480 msec to <500 msec
    1
        >=500 msec
    8
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Soluble c-Met Ectodomain and Hepatocyte Growth Factor Scatter Proteins

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    End point title
    Plasma Concentration of Soluble c-Met Ectodomain and Hepatocyte Growth Factor Scatter Proteins
    End point description
    Descriptive statistics (absolute value and change from baseline as measured by ratio to baseline) for each best overall response category (CR, PR, SD, PD or combined) have been used to summarize the data from optional soluble c-Met ectodomain assays for crizotinib treated patients.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1 of Cycle 1, 2 to 6 hours post-dose on Day 1 of Cycle 2, end of treatment (up to 112 weeks)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    172
    0 [8]
    Units: nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Baseline (N = 81)
    1428.3 ± 363.9
    ±
        Cycle 2 Day 1 6-hour post dose (N = 69)
    1683 ± 325.6
    ±
        End of treatment (N = 40)
    1751.8 ± 327.9
    ±
    Notes
    [8] - Participants from the SA population that received crizotinib were used for this analysis.
    No statistical analyses for this end point

    Secondary: Time to Deterioration (TTD) in Participant Reported Pain, Dyspnea, and Cough

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    End point title
    Time to Deterioration (TTD) in Participant Reported Pain, Dyspnea, and Cough
    End point description
    TTD in pain (pain in chest from European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Supplement Module for Lung Cancer [EORTC QLQ-LC13]), dyspnea (from EORTC QLQ-LC13), or cough (from EORTC QLQ-LC13) symptoms was defined as the time from randomization to the earliest time the participant's score showed a 10 point or higher increase from baseline in any of the three symptoms from the instrument. The transformed score of pain, dyspnea, and cough symptom scales of EORTC QLQ-LC13 range from 0 to 100, greater scores = higher symptom severity.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of treatment (up to 112 weeks)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    162
    151
    Units: months
        median (confidence interval 95%)
    4.5 (3 to 6.9)
    1.4 (1 to 1.6)
    Statistical analysis title
    TTD in Participant Reported Pain, Dyspnea & Cough
    Statistical analysis description
    The p-value was obtained from 2-sided unstratified log-rank test. The hazard ratio and corresponding 95% CI from the Cox Proportional Hazards model were also presented.
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    313
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.497
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.373
         upper limit
    0.661

    Secondary: European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)

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    End point title
    European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30)
    End point description
    EORTC QLQ-C30: included global health status/quality of life (QoL), functional scales (physical, role, cognitive, emotional, and social), symptom scales (fatigue, pain, nausea/vomiting), and single items (dyspnea, appetite loss, insomnia, constipation, diarrhea, and financial difficulties). Most questions used 4- point scale (1 'Not at All' to 4 'Very Much'); 2 questions used 7-point scale (1 'Very Poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score for Global Qol/functional scales=better level of QoL/functioning or higher score for symptom scale=greater degree of symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline, Day (D) 1 of each cycle (C) until disease progression, end of treatment (EOT, up to 112 weeks)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    165
    163
    Units: units on a scale
    arithmetic mean (standard deviation)
        Global QoL: Baseline (n=165, 162)
    57.2 ± 21.5
    58.1 ± 22.2
        Global QoL: C2D1 (n=154, 133)
    64.5 ± 21.8
    58.1 ± 23.1
        Global QoL: C3D1 (n=154, 106)
    65.2 ± 22.1
    59.4 ± 23.1
        Global QoL: C4D1 (n=135, 90)
    68.4 ± 19.6
    61.1 ± 20.8
        Global QoL: C5D1 (n=123, 74)
    68.5 ± 20.2
    64.1 ± 22.7
        Global QoL: C6D1 (n=120, 70)
    68.3 ± 19.8
    67.5 ± 23.5
        Global QoL: C7D1 (n=114, 52)
    69.5 ± 19.3
    66.5 ± 23.1
        Global QoL: C8D1 (n=110, 43)
    68.7 ± 20.1
    66.9 ± 25.3
        Global QoL: C9D1 (n=101, 37)
    68.7 ± 21
    66.4 ± 27.8
        Global QoL: C10D1 (n=94, 33)
    67 ± 21.6
    67.4 ± 26.8
        Global QoL: C11D1 (n=83, 25)
    69.5 ± 20.2
    71 ± 21.8
        Global QoL: C12D1 (n=76, 23)
    67.9 ± 22
    65.6 ± 24.1
        Global QoL: C13D1 (n=74, 21)
    66.8 ± 23.6
    66.7 ± 23.6
        Global QoL: C14D1 (n=66, 19)
    71.5 ± 20
    65.8 ± 23.4
        Global QoL: C15D1 (n=62, 16)
    69 ± 22.2
    66.1 ± 24.1
        Global QoL: C16D1 (n=53, 12)
    69.7 ± 18.1
    63.2 ± 25.5
        Global QoL: C17D1 (n=47, 11)
    67.6 ± 20.5
    69.7 ± 23.4
        Global QoL: C18D1 (n=44, 11)
    65.7 ± 19.9
    70.5 ± 22.5
        Global QoL: C19D1 (n=40, 9)
    69.2 ± 19.2
    72.2 ± 20
        Global QoL: C20D1 (n=35, 8)
    64.3 ± 20.6
    60.4 ± 21.2
        Global QoL: C21D1 (n=30, 8)
    65 ± 18.4
    63.5 ± 23.5
        Global QoL: C22D1 (n=24, 7)
    70.8 ± 19.3
    64.3 ± 24.9
        Global QoL: C23D1 (n=23, 4)
    67 ± 22.5
    50 ± 19.2
        Global QoL: C24D1 (n=20, 3)
    67.1 ± 18.8
    55.6 ± 19.2
        Global QoL: C25D1 (n=18, 3)
    67.1 ± 17.7
    61.1 ± 19.2
        Global QoL: C26D1 (n=14, 3)
    60.7 ± 22
    55.6 ± 12.7
        Global QoL: C27D1 (n=14, 2)
    58.9 ± 20.3
    41.7 ± 0
        Global QoL: C28D1 (n=11, 2)
    66.7 ± 18.3
    54.2 ± 17.7
        Global QoL: C29D1 (n=8, 2)
    59.4 ± 18.6
    41.7 ± 11.8
        Global QoL: C30D1 (n=8, 1)
    64.6 ± 19.3
    33.3 ± 0
        Global QoL: C31D1 (n=7, 0)
    64.3 ± 17.2
    0 ± 0
        Global QoL: C32D1 (n=6, 0)
    59.7 ± 17
    0 ± 0
        Global QoL: C33D1 (n=6, 0)
    66.7 ± 18.3
    0 ± 0
        Global QoL: C34D1 (n=5, 0)
    68.3 ± 14.9
    0 ± 0
        Global QoL: C35D1 (n=4, 0)
    60.4 ± 22.9
    0 ± 0
        Global QoL: C36D1 (n=1, 0)
    66.7 ± 0
    0 ± 0
        Global QoL: C37D1 (n=1, 0)
    66.7 ± 0
    0 ± 0
        Physical Functioning: Baseline (n=165, 163)
    76.3 ± 20.7
    75.8 ± 21.9
        Physical Functioning: C2D1 (n=155, 133)
    79.2 ± 20.9
    73.5 ± 22.3
        Physical Functioning: C3D1 (n=154, 106)
    82.3 ± 18.1
    75.5 ± 20.2
        Physical Functioning: C4D1 (n=135, 91)
    83.8 ± 16.2
    76.6 ± 20.2
        Physical Functioning: C5D1 (n=123, 74)
    84.5 ± 16.2
    78.6 ± 23
        Physical Functioning: C6D1 (n=120, 70)
    86.2 ± 16.7
    80.7 ± 19.7
        Physical Functioning: C7D1 (n=115, 52)
    86.7 ± 15
    80.3 ± 19.7
        Physical Functioning: C8D1 (n=111, 43)
    86.5 ± 16.3
    81.6 ± 18.5
        Physical Functioning: C9D1 (n=101, 37)
    87.7 ± 14.2
    82.3 ± 19.1
        Physical Functioning: C10D1 (n=94, 33)
    87.9 ± 14.8
    81.8 ± 20.7
        Physical Functioning: C11D1 (n=84, 25)
    87.2 ± 16.7
    83.2 ± 19
        Physical Functioning: C12D1 (n=76, 23)
    88.1 ± 15.3
    79.7 ± 22.8
        Physical Functioning: C13D1 (n=74, 21)
    89.3 ± 13.9
    78.4 ± 23.6
        Physical Functioning: C14D1 (n=66, 19)
    89 ± 14.3
    80 ± 21.4
        Physical Functioning: C15D1 (n=62, 16)
    87.8 ± 15.3
    82.9 ± 15.4
        Physical Functioning: C16D1 (n=53, 12)
    89.3 ± 11.5
    81.1 ± 19.5
        Physical Functioning: C17D1 (n=47, 11)
    86.6 ± 16.8
    81.8 ± 15.8
        Physical Functioning: C18D1 (n=45, 11)
    88.4 ± 13.3
    82.4 ± 16.1
        Physical Functioning: C19D1 (n=40, 9)
    88.3 ± 12.4
    81.5 ± 12.8
        Physical Functioning: C20D1 (n=35, 8)
    87.6 ± 12.7
    79.2 ± 17.3
        Physical Functioning: C21D1 (n=30, 8)
    88.4 ± 10.9
    77.5 ± 22.5
        Physical Functioning: C22D1 (n=24, 7)
    90.6 ± 8.3
    78.1 ± 24.3
        Physical Functioning: C23D1 (n=23, 4)
    88 ± 13.1
    60 ± 27.2
        Physical Functioning: C24D1 (n=20, 3)
    85 ± 14
    64.4 ± 32.9
        Physical Functioning: C25D1 (n=18, 3)
    87.4 ± 11.6
    60 ± 29.1
        Physical Functioning: C26D1 (n=14, 3)
    80.5 ± 25.3
    62.2 ± 30.8
        Physical Functioning: C27D1 (n=14, 2)
    78.6 ± 27.8
    50 ± 23.6
        Physical Functioning: C28D1 (n=11, 2)
    81.8 ± 24.1
    60 ± 18.9
        Physical Functioning: C29D1 (n=8, 2)
    85 ± 15
    46.7 ± 28.3
        Physical Functioning: C30D1 (n=8, 1)
    82.5 ± 21.4
    26.7 ± 0
        Physical Functioning: C31D1 (n=7, 0)
    83.8 ± 17.2
    0 ± 0
        Physical Functioning: C32D1 (n=6, 0)
    88.9 ± 9.1
    0 ± 0
        Physical Functioning: C33D1 (n=6, 0)
    90 ± 7
    0 ± 0
        Physical Functioning: C34D1 (n=5, 0)
    85.3 ± 7.3
    0 ± 0
        Physical Functioning: C35D1 (n=4, 0)
    91.7 ± 3.3
    0 ± 0
        Physical Functioning: C36D1 (n=1, 0)
    86.7 ± 0
    0 ± 0
        Physical Functioning: C37D1 (n=1, 0)
    86.7 ± 0
    0 ± 0
        Role Functioning: Baseline (n=165, 163)
    69.3 ± 28.7
    66.6 ± 30.2
        Role Functioning: C2D1 (n=155, 133)
    73.8 ± 28.9
    64.7 ± 29.7
        Role Functioning: C3D1 (n=154, 106)
    74.4 ± 28.6
    65.3 ± 27.7
        Role Functioning: C4D1 (n=134, 91)
    77.9 ± 25.7
    67.2 ± 27.3
        Role Functioning: C5D1 (n=123, 74)
    78.2 ± 24.3
    69.6 ± 27.4
        Role Functioning: C6D1 (n=120, 70)
    80 ± 24.1
    69.5 ± 26.2
        Role Functioning: C7D1 (n=115, 52)
    81.7 ± 22.6
    72.1 ± 25.9
        Role Functioning: C8D1 (n=111, 43)
    80.4 ± 23.9
    75.2 ± 28.3
        Role Functioning: C9D1 (n=101, 37)
    80.9 ± 25.8
    76.6 ± 27.6
        Role Functioning: C10D1 (n=94, 33)
    81.6 ± 23.1
    75.3 ± 28.3
        Role Functioning: C11D1 (n=84, 25)
    81.3 ± 23.8
    75.3 ± 25.5
        Role Functioning: C12D1 (n=76, 23)
    81.6 ± 23.2
    72.5 ± 29.6
        Role Functioning: C13D1 (n=74, 21)
    80.2 ± 25.5
    68.3 ± 32
        Role Functioning: C14D1 (n=66, 19)
    83.8 ± 21.3
    68.4 ± 30.4
        Role Functioning: C15D1 (n=62, 16)
    80.6 ± 24
    77.1 ± 27.8
        Role Functioning: C16D1 (n=53, 12)
    84 ± 19
    69.4 ± 34
        Role Functioning: C17D1 (n=47, 11)
    77.7 ± 25.4
    71.2 ± 38.1
        Role Functioning: C18D1 (n=45, 11)
    80 ± 22.4
    71.2 ± 31.7
        Role Functioning: C19D1 (n=40, 9)
    82.1 ± 19.4
    74.1 ± 29
        Role Functioning: C20D1 (n=35, 8)
    81.9 ± 17.8
    70.8 ± 36.5
        Role Functioning: C21D1 (n=30, 8)
    80 ± 24.1
    66.7 ± 32.1
        Role Functioning: C22D1 (n=24, 7)
    84.7 ± 19
    67.9 ± 33.5
        Role Functioning: C23D1 (n=23, 4)
    76.8 ± 26.9
    37.5 ± 25
        Role Functioning: C24D1 (n=20, 3)
    80.8 ± 24.3
    44.4 ± 38.5
        Role Functioning: C25D1 (n=18, 3)
    87 ± 19.4
    44.4 ± 25.5
        Role Functioning: C26D1 (n=14, 3)
    75 ± 29.1
    33.3 ± 33.3
        Role Functioning: C27D1 (n=14, 2)
    69 ± 35.1
    25 ± 11.8
        Role Functioning: C28D1 (n=11, 2)
    77.3 ± 33.6
    25 ± 35.4
        Role Functioning: C29D1 (n=8, 2)
    77.1 ± 34.4
    25 ± 11.8
        Role Functioning: C30D1 (n=8, 1)
    77.1 ± 34.4
    0 ± 0
        Role Functioning: C31D1 (n=7, 0)
    71.4 ± 36.9
    0 ± 0
        Role Functioning: C32D1 (n=6, 0)
    86.1 ± 12.5
    0 ± 0
        Role Functioning: C33D1 (n=6, 0)
    88.9 ± 13.6
    0 ± 0
        Role Functioning: C34D1 (n=5, 0)
    96.7 ± 7.5
    0 ± 0
        Role Functioning: C35D1 (n=4, 0)
    91.7 ± 16.7
    0 ± 0
        Role Functioning: C36D1 (n=1, 0)
    100 ± 0
    0 ± 0
        Role Functioning: C37D1 (n=1, 0)
    100 ± 0
    0 ± 0
        Emotional Functioning: Baseline (n=165, 162)
    74.5 ± 21.3
    73.7 ± 20.7
        Emotional Functioning: C2D1 (n=155, 133)
    83.1 ± 18.7
    77.7 ± 19.3
        Emotional Functioning: C3D1 (n=154, 106)
    83.3 ± 16.7
    77.9 ± 21.5
        Emotional Functioning: C4D1 (n=135, 90)
    84.1 ± 17.3
    80.5 ± 18.9
        Emotional Functioning: C5D1 (n=123, 74)
    83 ± 19.1
    79.8 ± 19.9
        Emotional Functioning: C6D1 (n=120, 70)
    85.3 ± 17.8
    81.2 ± 19.4
        Emotional Functioning: C7D1 (n=115, 52)
    86.4 ± 16.5
    81.9 ± 17.6
        Emotional Functioning: C8D1 (n=111, 43)
    83.9 ± 19.8
    81.6 ± 20.7
        Emotional Functioning: C9D1 (n=101, 37)
    84.4 ± 19
    82.4 ± 19.6
        Emotional Functioning: C10D1 (n=94, 33)
    87.2 ± 16.8
    81.8 ± 21.2
        Emotional Functioning: C11D1 (n=84,25)
    86.1 ± 16.7
    85 ± 17.8
        Emotional Functioning: C12D1 (n=76, 23)
    85.3 ± 18.6
    84.8 ± 18.6
        Emotional Functioning: C13D1 (n=74, 21)
    84.9 ± 19
    80.6 ± 19.1
        Emotional Functioning: C14D1 (n=66, 19)
    84.5 ± 19.9
    81.6 ± 21.1
        Emotional Functioning: C15D1 (n=62, 16)
    86.3 ± 18
    82.3 ± 18.2
        Emotional Functioning: C16D1 (n=53, 12)
    85.8 ± 17.6
    77.8 ± 27.8
        Emotional Functioning: C17D1 (n=47, 11)
    85.6 ± 22
    79.5 ± 23.4
        Emotional Functioning: C18D1 (n=44, 11)
    86.4 ± 17.2
    75.8 ± 27.8
        Emotional Functioning: C19D1 (n=40, 9)
    87.3 ± 16
    81.5 ± 20.7
        Emotional Functioning: C20D1 (n=35, 8)
    83.8 ± 17.5
    82.3 ± 25
        Emotional Functioning: C21D1 (n=30, 8)
    84.5 ± 17.1
    80.2 ± 29.5
        Emotional Functioning: C22D1 (n=24, 7)
    83.7 ± 21.6
    78.6 ± 24.9
        Emotional Functioning: C23D1 (n=23, 4)
    84.1 ± 19.8
    70.8 ± 21
        Emotional Functioning: C24D1 (n=20, 3)
    87.9 ± 16.1
    66.7 ± 30
        Emotional Functioning: C25D1 (n=18, 3)
    81.5 ± 19.5
    72.2 ± 24.1
        Emotional Functioning: C26D1 (n=14, 3)
    73.2 ± 28.3
    72.2 ± 24.1
        Emotional Functioning: C27D1 (n=14, 2)
    70.8 ± 27.3
    58.3 ± 0
        Emotional Functioning: C28D1 (n=11, 2)
    81.1 ± 27.2
    58.3 ± 0
        Emotional Functioning: C29D1 (n=8, 2)
    86.5 ± 15.4
    54.2 ± 5.9
        Emotional Functioning: C30D1 (n=8, 1)
    84.4 ± 25
    58.3 ± 0
        Emotional Functioning: C31D1 (n=7, 0)
    76.2 ± 28.2
    0 ± 0
        Emotional Functioning: C32D1 (n=6, 0)
    87.5 ± 17.3
    0 ± 0
        Emotional Functioning: C33D1 (n=6, 0)
    90.3 ± 13.4
    0 ± 0
        Emotional Functioning: C34D1 (n=5, 0)
    91.7 ± 14.4
    0 ± 0
        Emotional Functioning: C35D1 (n=4, 0)
    83.3 ± 20.4
    0 ± 0
        Emotional Functioning: C36D1 (n=1, 0)
    58.3 ± 0
    0 ± 0
        Emotional Functioning: C37D1 (n=1, 0)
    58.3 ± 0
    0 ± 0
        Cognitive Functioning: Baseline (n=165, 162)
    85.6 ± 18.3
    83.6 ± 22.3
        Cognitive Functioning: C2D1 (n=155, 133)
    85.5 ± 18.9
    84.5 ± 20.6
        Cognitive Functioning: C3D1 (n=154, 106)
    87 ± 15.7
    83.8 ± 20.4
        Cognitive Functioning: C4D1 (n=135, 90)
    88.1 ± 15.6
    82.6 ± 20.4
        Cognitive Functioning: C5D1 (n=123, 74)
    88.9 ± 14.4
    82.7 ± 22
        Cognitive Functioning: C6D1 (n=120, 70)
    87.5 ± 15.3
    83.8 ± 19.2
        Cognitive Functioning: C7D1 (n=115, 52)
    86.7 ± 15.6
    85.3 ± 18.3
        Cognitive Functioning: C8D1 (n=111, 43)
    87.8 ± 14.7
    82.2 ± 23.4
        Cognitive Functioning: C9D1 (n=101, 37)
    88.3 ± 16.6
    84.7 ± 21.7
        Cognitive Functioning: C10D1 (n=94, 33)
    89.2 ± 16
    80.8 ± 22.1
        Cognitive Functioning: C11D1 (n=84, 25)
    87.9 ± 14.9
    85.3 ± 19.4
        Cognitive Functioning: C12D1 (n=76, 23)
    89.5 ± 14.4
    80.4 ± 22.8
        Cognitive Functioning: C13D1 (n=74, 21)
    88.5 ± 15.6
    79.4 ± 27.8
        Cognitive Functioning: C14D1 (n=66, 19)
    88.9 ± 14.7
    81.6 ± 24.1
        Cognitive Functioning: C15D1 (n=62, 16)
    87.6 ± 15.4
    84.4 ± 18.7
        Cognitive Functioning: C16D1 (n=53, 12)
    87.4 ± 14.2
    72.2 ± 25.9
        Cognitive Functioning: C17D1 (n=47, 11)
    85.1 ± 15.2
    75.8 ± 21.6
        Cognitive Functioning: C18D1 (n=44, 11)
    88.3 ± 14.6
    75.8 ± 25.1
        Cognitive Functioning: C19D1 (n=40, 9)
    87.5 ± 14.5
    70.4 ± 23.2
        Cognitive Functioning: C20D1 (n=35, 8)
    85.7 ± 15.2
    72.9 ± 23.5
        Cognitive Functioning: C21D1 (n=30, 8)
    85.6 ± 15
    72.9 ± 23.5
        Cognitive Functioning: C22D1 (n=24, 7)
    86.1 ± 15.3
    69 ± 24.4
        Cognitive Functioning: C23D1 (n=23, 4)
    85.5 ± 14.5
    58.3 ± 21.5
        Cognitive Functioning: C24D1 (n=20, 3)
    85.8 ± 19.7
    61.1 ± 34.7
        Cognitive Functioning: C25D1 (n=18, 3)
    86.1 ± 15.4
    55.6 ± 25.5
        Cognitive Functioning: C26D1 (n=14, 3)
    81 ± 26
    61.1 ± 34.7
        Cognitive Functioning: C27D1 (n=14, 2)
    76.2 ± 25.9
    41.7 ± 11.8
        Cognitive Functioning: C28D1 (n=11, 2)
    78.8 ± 21.2
    41.7 ± 11.8
        Cognitive Functioning: C29D1 (n=8, 2)
    87.5 ± 11.8
    33.3 ± 0
        Cognitive Functioning: C30D1 (n=8, 1)
    83.3 ± 23.6
    16.7 ± 0
        Cognitive Functioning: C31D1 (n=7, 0)
    81 ± 20.2
    0 ± 0
        Cognitive Functioning: C32D1 (n=6, 0)
    83.3 ± 18.3
    0 ± 0
        Cognitive Functioning: C33D1 (n=6, 0)
    86.1 ± 16.4
    0 ± 0
        Cognitive Functioning: C34D1 (n=5, 0)
    90 ± 9.1
    0 ± 0
        Cognitive Functioning: C35D1 (n=4, 0)
    95.8 ± 8.3
    0 ± 0
        Cognitive Functioning: C36D1 (n=1, 0)
    100 ± 0
    0 ± 0
        Cognitive Functioning: C37D1 (n=1, 0)
    83.3 ± 0
    0 ± 0
        Social Functioning: Baseline (n=165, 162)
    68 ± 27.7
    67.1 ± 29
        Social Functioning: C2D1 (n=155, 133)
    75.9 ± 25.1
    69.5 ± 28.1
        Social Functioning: C3D1 (n=154, 106)
    78.5 ± 24
    72.5 ± 26.7
        Social Functioning: C4D1 (n=135, 90)
    79.4 ± 23.9
    71.7 ± 26.3
        Social Functioning: C5D1 (n=123, 74)
    79.4 ± 23.8
    74.5 ± 27.1
        Social Functioning: C6D1 (n=120, 70)
    81.8 ± 22.1
    76.4 ± 27.3
        Social Functioning: C7D1 (n=115, 52)
    82.3 ± 21.8
    77.9 ± 24.6
        Social Functioning: C8D1 (n=111, 43)
    82 ± 21.3
    77.5 ± 24.4
        Social Functioning: C9D1 (n=101, 37)
    80.4 ± 24.7
    80.2 ± 21.8
        Social Functioning: C10D1 (n=94, 33)
    81.9 ± 25.1
    76.3 ± 27
        Social Functioning: C11D1 (n=84, 25)
    81.9 ± 23
    78.7 ± 24.8
        Social Functioning: C12D1 (n=76, 23)
    82 ± 23.5
    71 ± 31.9
        Social Functioning: C13D1 (n=74, 21)
    81.8 ± 24.7
    71.4 ± 28.9
        Social Functioning: C14D1 (n=66, 19)
    81.3 ± 23.8
    69.3 ± 34.8
        Social Functioning: C15D1 (n=62, 16)
    81.5 ± 25.6
    74 ± 28.5
        Social Functioning: C16D1 (n=53, 12)
    82.7 ± 21.9
    65.3 ± 35.9
        Social Functioning: C17D1 (n=47, 11)
    81.9 ± 24.8
    69.7 ± 33.2
        Social Functioning: C18D1 (n=44, 11)
    82.6 ± 22.7
    65.2 ± 35.3
        Social Functioning: C19D1 (n=40, 9)
    84.6 ± 22.8
    64.8 ± 31.7
        Social Functioning: C20D1 (n=35, 8)
    82.9 ± 23.7
    70.8 ± 33
        Social Functioning: C21D1 (n=30, 8)
    82.8 ± 24.2
    64.6 ± 36.1
        Social Functioning: C22D1 (n=24, 7)
    82.6 ± 23.8
    65.5 ± 39.8
        Social Functioning: C23D1 (n=23, 4)
    84.4 ± 23.9
    41.7 ± 50
        Social Functioning: C24D1 (n=20, 3)
    84.2 ± 27.3
    61.1 ± 53.6
        Social Functioning: C25D1 (n=18, 3)
    89.8 ± 19.1
    50 ± 50
        Social Functioning: C26D1 (n=14, 3)
    78.6 ± 28.8
    50 ± 50
        Social Functioning: C27D1 (n=14, 2)
    85.7 ± 15.8
    33.3 ± 47.1
        Social Functioning: C28D1 (n=11, 2)
    83.3 ± 26.9
    33.3 ± 47.1
        Social Functioning: C29D1 (n=8, 2)
    83.3 ± 25.2
    33.3 ± 47.1
        Social Functioning: C30D1 (n=8, 1)
    85.4 ± 24.3
    0 ± 0
        Social Functioning: C31D1 (n=7, 0)
    73.8 ± 38.3
    0 ± 0
        Social Functioning: C32D1 (n=6, 0)
    83.3 ± 18.3
    0 ± 0
        Social Functioning: C33D1 (n=6, 0)
    94.4 ± 13.6
    0 ± 0
        Social Functioning: C34D1 (n=5, 0)
    96.7 ± 7.5
    0 ± 0
        Social Functioning: C35D1 (n=4, 0)
    91.7 ± 16.7
    0 ± 0
        Social Functioning: C36D1 (n=1, 0)
    66.7 ± 0
    0 ± 0
        Social Functioning: C37D1 (n=1, 0)
    66.7 ± 0
    0 ± 0
        Fatigue: Baseline (n=165, 163)
    38.3 ± 24.4
    36.1 ± 25.3
        Fatigue: C2D1 (n=155, 133)
    31.4 ± 23.4
    39.5 ± 24.8
        Fatigue: C3D1 (n=154, 106)
    30.8 ± 24.1
    39.4 ± 24.5
        Fatigue: C4D1 (n=135, 91)
    27.1 ± 22.3
    34.1 ± 22.1
        Fatigue: C5D1 (n=123, 74)
    24.7 ± 19.8
    31.5 ± 25.2
        Fatigue: C6D1 (n=120, 70)
    24.6 ± 19.3
    31 ± 22.8
        Fatigue: C7D1 (n=115, 52)
    23.9 ± 19.8
    27.6 ± 23.1
        Fatigue: C8D1 (n=111, 43)
    23.2 ± 18.9
    26.6 ± 23.6
        Fatigue: C9D1 (n=101, 37)
    22.9 ± 21.7
    28.5 ± 26.6
        Fatigue: C10D1 (n=94, 33)
    21.4 ± 20
    28.6 ± 27.9
        Fatigue: C11D1 (n=84, 25)
    22.1 ± 19.6
    22.2 ± 22.9
        Fatigue: C12D1 (n=76, 23)
    21.9 ± 22.9
    26.1 ± 24.1
        Fatigue: C13D1 (n=74, 21)
    23.3 ± 21.3
    27.5 ± 25.2
        Fatigue: C14D1 (n=66, 19)
    21.7 ± 21.7
    28.1 ± 26.8
        Fatigue: C15D1 (n=62, 16)
    20.8 ± 22.5
    24.3 ± 24.8
        Fatigue: C16D1 (n=53, 12)
    22.2 ± 18
    24.1 ± 21.6
        Fatigue: C17D1 (n=47, 11)
    23.4 ± 20
    23.2 ± 23
        Fatigue: C18D1 (n=45, 11)
    21.5 ± 18.3
    27.3 ± 22.4
        Fatigue: C19D1 (n=40, 9)
    20.8 ± 18.7
    24.7 ± 20.6
        Fatigue: C20D1 (n=35, 8)
    24.4 ± 19.2
    27.8 ± 26.6
        Fatigue: C21D1 (n=30, 8)
    23.9 ± 17.8
    25.7 ± 27.7
        Fatigue: C22D1 (n=24, 7)
    23.6 ± 16.2
    27 ± 23.9
        Fatigue: C23D1 (n=23, 4)
    25.1 ± 19.3
    47.2 ± 14
        Fatigue: C24D1 (n=20, 3)
    24.4 ± 18.9
    40.7 ± 23.1
        Fatigue: C25D1 (n=18, 3)
    24.7 ± 16
    44.4 ± 19.2
        Fatigue: C26D1 (n=14, 3)
    30.2 ± 25.6
    44.4 ± 19.2
        Fatigue: C27D1 (n=14, 2)
    35.7 ± 25.1
    55.6 ± 15.7
        Fatigue: C28D1 (n=11, 2)
    28.3 ± 22.4
    38.9 ± 7.9
        Fatigue: C29D1 (n=8, 2)
    30.6 ± 22.8
    50 ± 23.6
        Fatigue: C30D1 (n=8, 1)
    26.4 ± 24.4
    55.6 ± 0
        Fatigue: C31D1 (n=7, 0)
    28.6 ± 16.8
    0 ± 0
        Fatigue: C32D1 (n=6, 0)
    25.9 ± 5.7
    0 ± 0
        Fatigue: C33D1 (n=6, 0)
    18.5 ± 11.5
    0 ± 0
        Fatigue: C34D1 (n=5, 0)
    15.6 ± 16.9
    0 ± 0
        Fatigue: C35D1 (n=4, 0)
    27.8 ± 14.3
    0 ± 0
        Fatigue: C36D1 (n=1, 0)
    33.3 ± 0
    0 ± 0
        Fatigue: C37D1 (n=1, 0)
    11.1 ± 0
    0 ± 0
        Nausea and Vomiting: Baseline (n=165, 163)
    8.4 ± 14.4
    11.7 ± 18
        Nausea and Vomiting: C2D1 (n=155, 133)
    15.2 ± 20.9
    12.7 ± 19
        Nausea and Vomiting: C3D1 (n=154, 106)
    13.9 ± 21.2
    9.9 ± 16.6
        Nausea and Vomiting: C4D1 (n=135, 91)
    9.9 ± 18.1
    8.1 ± 14.1
        Nausea and Vomiting: C5D1 (n=123, 74)
    9.2 ± 14.7
    9 ± 16.8
        Nausea and Vomiting: C6D1 (n=120, 70)
    10.1 ± 15.2
    6.9 ± 13.2
        Nausea and Vomiting: C7D1 (n=115, 52)
    7.1 ± 11.9
    7.7 ± 11.7
        Nausea and Vomiting: C8D1 (n=111, 43)
    8.8 ± 13.7
    8.9 ± 14.7
        Nausea and Vomiting: C9D1 (n=101, 37)
    6.9 ± 13
    9.5 ± 19.9
        Nausea and Vomiting: C10D1 (n=94, 33)
    8.5 ± 14.6
    8.1 ± 15.7
        Nausea and Vomiting: C11D1 (n=84, 25)
    8.3 ± 12.8
    8 ± 16
        Nausea and Vomiting: C12D1 (n=76, 23)
    6.4 ± 12.8
    7.2 ± 15.8
        Nausea and Vomiting: C13D1 (n=74, 21)
    8.6 ± 14.1
    7.1 ± 16.3
        Nausea and Vomiting: C14D1 (n=66, 19)
    5.8 ± 13.9
    7 ± 14
        Nausea and Vomiting: C15D1 (n=62, 16)
    5.9 ± 11.3
    6.2 ± 13.4
        Nausea and Vomiting: C16D1 (n=53, 12)
    5.3 ± 9.7
    6.9 ± 11.1
        Nausea and Vomiting: C17D1 (n=47, 11)
    7.8 ± 12.5
    10.6 ± 11.2
        Nausea and Vomiting: C18D1 (n=45, 11)
    7 ± 13.5
    3 ± 6.7
        Nausea and Vomiting: C19D1 (n=40, 9)
    8.8 ± 14.6
    9.3 ± 12.1
        Nausea and Vomiting: C20D1 (n=35, 8)
    7.4 ± 13.5
    10.4 ± 15.3
        Nausea and Vomiting: C21D1 (n=30, 8)
    7.8 ± 12.9
    8.3 ± 12.6
        Nausea and Vomiting: C22D1 (n=24, 7)
    2.8 ± 6.3
    14.3 ± 17.8
        Nausea and Vomiting: C23D1 (n=23, 4)
    5.4 ± 10.5
    45.8 ± 21
        Nausea and Vomiting: C24D1 (n=20, 3)
    7.5 ± 14.8
    33.3 ± 28.9
        Nausea and Vomiting: C25D1 (n=18, 3)
    3.7 ± 9.1
    27.8 ± 25.5
        Nausea and Vomiting: C26D1 (n=14, 3)
    10.7 ± 27.4
    33.3 ± 16.7
        Nausea and Vomiting: C27D1 (n=14, 2)
    11.9 ± 27.3
    33.3 ± 23.6
        Nausea and Vomiting: C28D1 (n=11, 2)
    3 ± 6.7
    25 ± 11.8
        Nausea and Vomiting: C29D1 (n=8, 2)
    10.4 ± 15.3
    25 ± 11.8
        Nausea and Vomiting: C30D1 (n=8, 1)
    6.3 ± 12.4
    33.3 ± 0
        Nausea and Vomiting: C31D1 (n=7, 0)
    14.3 ± 17.8
    0 ± 0
        Nausea and Vomiting: C32D1 (n=6, 0)
    11.1 ± 17.2
    0 ± 0
        Nausea and Vomiting: C33D1 (n=6, 0)
    11.1 ± 17.2
    0 ± 0
        Nausea and Vomiting: C34D1 (n=5, 0)
    13.3 ± 18.3
    0 ± 0
        Nausea and Vomiting: C35D1 (n=4, 0)
    12.5 ± 16
    0 ± 0
        Nausea and Vomiting: C36D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Nausea and Vomiting: C37D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Pain: Baseline (n=165, 163)
    23.9 ± 24.7
    28 ± 27.3
        Pain: C2D1 (n=155, 133)
    13.9 ± 19.8
    25.7 ± 25.3
        Pain: C3D1 (n=154, 106)
    13.7 ± 20.4
    23.3 ± 26.6
        Pain: C4D1 (n=135, 91)
    13 ± 19.5
    19 ± 21.5
        Pain: C5D1 (n=123, 74)
    11.5 ± 16.7
    20.5 ± 23
        Pain: C6D1 (n=120, 70)
    10.6 ± 15
    19.5 ± 23
        Pain: C7D1 (n=115, 52)
    9.6 ± 14.3
    21.5 ± 24.3
        Pain: C8D1 (n=111, 43)
    11.3 ± 18
    17.4 ± 23.6
        Pain: C9D1 (n=101, 37)
    11.8 ± 18.8
    23 ± 27.6
        Pain: C10D1 (n=94, 33)
    8.7 ± 14
    24.2 ± 28.6
        Pain: C11D1 (n=84, 25)
    10.5 ± 16.3
    22 ± 27.9
        Pain: C12D1 (n=76, 23)
    8.6 ± 14.3
    25.4 ± 29.7
        Pain: C13D1 (n=74, 21)
    10.1 ± 15.3
    27.8 ± 30.4
        Pain: C14D1 (n=66, 19)
    8.1 ± 12.8
    23.7 ± 26.2
        Pain: C15D1 (n=62, 16)
    9.4 ± 15.6
    22.9 ± 25.7
        Pain: C16D1 (n=53, 12)
    9.4 ± 14.4
    31.9 ± 28.8
        Pain: C17D1 (n=47, 11)
    10.6 ± 16.1
    24.2 ± 27.2
        Pain: C18D1 (n=45, 11)
    11.1 ± 18.1
    24.2 ± 29.2
        Pain: C19D1 (n=40, 9)
    11.3 ± 17
    24.1 ± 20.6
        Pain: C20D1 (n=35, 8)
    11.9 ± 18.8
    22.9 ± 28.1
        Pain: C21D1 (n=30, 8)
    11.7 ± 15.3
    29.2 ± 30.5
        Pain: C22D1 (n=24, 7)
    6.9 ± 12.9
    33.3 ± 28.9
        Pain: C23D1 (n=23, 4)
    9.1 ± 16.1
    33.3 ± 36
        Pain: C24D1 (n=20, 3)
    4.2 ± 11.9
    27.8 ± 48.1
        Pain: C25D1 (n=18, 3)
    4.6 ± 7.7
    38.9 ± 41.9
        Pain: C26D1 (n=14, 3)
    17.9 ± 27.3
    38.9 ± 41.9
        Pain: C27D1 (n=14, 2)
    13.1 ± 25.5
    58.3 ± 35.4
        Pain: C28D1 (n=11, 2)
    4.5 ± 7.8
    50 ± 47.1
        Pain: C29D1 (n=8, 2)
    2.1 ± 5.9
    41.7 ± 35.4
        Pain: C30D1 (n=8, 1)
    4.2 ± 7.7
    83.3 ± 0
        Pain: C31D1 (n=7, 0)
    4.8 ± 8.1
    0 ± 0
        Pain: C32D1 (n=6, 0)
    5.6 ± 8.6
    0 ± 0
        Pain: C33D1 (n=6, 0)
    2.8 ± 6.8
    0 ± 0
        Pain: C34D1 (n=5, 0)
    3.3 ± 7.5
    0 ± 0
        Pain: C35D1 (n=4, 0)
    8.3 ± 16.7
    0 ± 0
        Pain: C36D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Pain: C37D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Dyspnea: Baseline (n=165, 163)
    31.1 ± 28.3
    32.5 ± 28.2
        Dyspnea: C2D1 (n=155, 133)
    21.5 ± 21.4
    33.6 ± 27.7
        Dyspnea: C3D1 (n=154, 106)
    21.6 ± 23
    33.3 ± 28.4
        Dyspnea: C4D1 (n=135, 91)
    17.3 ± 20.7
    29.3 ± 26.2
        Dyspnea: C5D1 (n=123, 74)
    16 ± 20.6
    29.3 ± 24
        Dyspnea: C6D1 (n=120, 70)
    15.8 ± 22
    26.2 ± 24.7
        Dyspnea: C7D1 (n=115, 52)
    17.4 ± 20.9
    28.2 ± 22.3
        Dyspnea: C8D1 (n=111, 43)
    15.8 ± 19.7
    22.5 ± 28.8
        Dyspnea: C9D1 (n=101, 37)
    13.9 ± 19
    23.4 ± 24.7
        Dyspnea: C10D1 (n=94, 33)
    17.7 ± 20.6
    24.2 ± 22.5
        Dyspnea: C11D1 (n=84, 25)
    17.5 ± 22.8
    25.3 ± 22.1
        Dyspnea: C12D1 (n=76, 23)
    14.5 ± 19.9
    30.4 ± 28.3
        Dyspnea: C13D1 (n=74, 21)
    14 ± 20.6
    23.8 ± 23.9
        Dyspnea: C14D1 (n=66, 19)
    15.2 ± 21.2
    29.8 ± 24.6
        Dyspnea: C15D1 (n=62, 16)
    15.6 ± 21.5
    20.8 ± 20.6
        Dyspnea: C16D1 (n=53, 12)
    13.8 ± 17.8
    19.4 ± 22.3
        Dyspnea: C17D1 (n=46, 11)
    14.5 ± 20.7
    24.2 ± 21.6
        Dyspnea: C18D1 (n=45, 11)
    14.1 ± 16.6
    24.2 ± 26.2
        Dyspnea: C19D1 (n=40, 9)
    14.2 ± 18.3
    25.9 ± 22.2
        Dyspnea: C20D1 (n=35, 8)
    10.5 ± 17.7
    33.3 ± 25.2
        Dyspnea: C21D1 (n=30, 8)
    13.3 ± 16.6
    33.3 ± 17.8
        Dyspnea: C22D1 (n=24, 7)
    13.9 ± 19.5
    28.6 ± 23
        Dyspnea: C23D1 (n=23, 4)
    9.4 ± 14.9
    41.7 ± 16.7
        Dyspnea: C24D1 (n=20, 3)
    18.3 ± 20.2
    44.4 ± 19.2
        Dyspnea: C25D1 (n=18, 3)
    11.1 ± 16.2
    33.3 ± 33.3
        Dyspnea: C26D1 (n=14, 3)
    14.3 ± 28.4
    33.3 ± 33.3
        Dyspnea: C27D1 (n=14, 2)
    11.9 ± 16.6
    50 ± 23.6
        Dyspnea: C28D1 (n=11, 2)
    12.1 ± 16.8
    50 ± 23.6
        Dyspnea: C29D1 (n=8, 2)
    4.2 ± 11.8
    50 ± 23.6
        Dyspnea: C30D1 (n=8, 1)
    8.3 ± 15.4
    66.7 ± 0
        Dyspnea: C31D1 (n=7, 0)
    9.5 ± 16.3
    0 ± 0
        Dyspnea: C32D1 (n=6, 0)
    16.7 ± 18.3
    0 ± 0
        Dyspnea: C33D1 (n=6, 0)
    11.1 ± 17.2
    0 ± 0
        Dyspnea: C34D1 (n=5, 0)
    13.3 ± 18.3
    0 ± 0
        Dyspnea: C35D1 (n=4, 0)
    16.7 ± 19.2
    0 ± 0
        Dyspnea: C36D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Dyspnea: C37D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Insomnia : Baseline (n=164, 163)
    22.6 ± 26.4
    27.8 ± 27.3
        Insomnia : C2D1 (n=155, 133)
    15.3 ± 23.5
    27.1 ± 25.3
        Insomnia : C3D1 (n=154, 106)
    16.2 ± 26.2
    23.6 ± 26
        Insomnia : C4D1 (n=135, 91)
    13.3 ± 21.2
    23.8 ± 26.9
        Insomnia : C5D1 (n=123, 74)
    13.6 ± 21.3
    25.7 ± 26.8
        Insomnia : C6D1 (n=120, 70)
    14.2 ± 21.9
    23.3 ± 25
        Insomnia : C7D1 (n=114, 52)
    9.4 ± 17.5
    21.8 ± 25.5
        Insomnia : C8D1 (n=111, 43)
    12.5 ± 21.5
    21.7 ± 22.9
        Insomnia : C9D1 (n=100, 37)
    12.3 ± 21.5
    22.5 ± 24.9
        Insomnia : C10D1 (n=94, 33)
    13.5 ± 23.6
    24.2 ± 25.4
        Insomnia : C11D1 (n=84, 25)
    13.9 ± 22.1
    22.7 ± 24.9
        Insomnia : C12D1 (n=76, 23)
    13.6 ± 21.9
    23.2 ± 25.5
        Insomnia : C13D1 (n=74, 21)
    10.8 ± 19.2
    25.4 ± 25.6
        Insomnia : C14D1 (n=66, 19)
    11.1 ± 18.8
    24.6 ± 29.1
        Insomnia : C15D1 (n=62, 16)
    11.3 ± 20
    29.2 ± 26.9
        Insomnia : C16D1 (n=53, 11)
    13.8 ± 20.1
    21.2 ± 22.5
        Insomnia : C17D1 (n=47, 11)
    13.5 ± 21.6
    15.2 ± 22.9
        Insomnia : C18D1 (n=45, 11)
    12.6 ± 17.8
    21.2 ± 27
        Insomnia : C19D1 (n=40, 9)
    13.3 ± 19.7
    22.2 ± 28.9
        Insomnia : C20D1 (n=35, 8)
    15.2 ± 20.4
    20.8 ± 24.8
        Insomnia : C21D1 (n=30, 8)
    12.2 ± 18.5
    29.2 ± 27.8
        Insomnia : C22D1 (n=24, 7)
    12.5 ± 19.2
    31 ± 24.4
        Insomnia : C23D1 (n=23, 4)
    17.4 ± 26.3
    50 ± 19.2
        Insomnia : C24D1 (n=20, 3)
    11.7 ± 22.4
    22.2 ± 38.5
        Insomnia : C25D1 (n=18, 3)
    20.4 ± 30.5
    44.4 ± 19.2
        Insomnia : C26D1 (n=14, 3)
    21.4 ± 33.6
    22.2 ± 38.5
        Insomnia : C27D1 (n=14, 2)
    16.7 ± 21.7
    50 ± 23.6
        Insomnia : C28D1 (n=11, 2)
    9.1 ± 15.6
    50 ± 23.6
        Insomnia : C29D1 (n=8, 2)
    8.3 ± 15.4
    33 ± 0
        Insomnia : C30D1 (n=8, 1)
    12.5 ± 24.8
    33.3 ± 0
        Insomnia : C31D1 (n=7, 0)
    0 ± 0
    0 ± 0
        Insomnia : C32D1 (n=6, 0)
    5.6 ± 13.6
    0 ± 0
        Insomnia : C33D1 (n=6, 0)
    5.6 ± 13.6
    0 ± 0
        Insomnia : C34D1 (n=5, 0)
    13.3 ± 18.3
    0 ± 0
        Insomnia : C35D1 (n=4, 0)
    16.7 ± 19.2
    0 ± 0
        Insomnia : C36D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Insomnia : C37D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Appetite loss : Baseline(n=165, 163)
    24.4 ± 28.8
    23.3 ± 28.2
        Appetite loss : C2/D1(n=155, 133)
    21.1 ± 30.2
    24.3 ± 28.5
        Appetite loss : C3/D1(n=154, 106)
    18.4 ± 29
    21.7 ± 27.2
        Appetite loss : C4/D1(n=135, 91)
    14.6 ± 24.3
    19.4 ± 23.3
        Appetite loss : C5/D1(n=123, 74)
    12.7 ± 22.4
    19.4 ± 28.1
        Appetite loss : C6/D1(n=120, 70)
    13.6 ± 21.8
    12.9 ± 23.6
        Appetite loss : C7/D1(n=115, 52)
    10.4 ± 19.4
    12.8 ± 22
        Appetite loss : C8/D1(n=111, 43)
    12.8 ± 20.8
    10.9 ± 22.7
        Appetite loss : C9/D1(n=101, 37)
    12.2 ± 239
    14.4 ± 27.8
        Appetite loss : C10/D1(n=94, 33)
    12.4 ± 22.9
    14.1 ± 25
        Appetite loss : C11/D1(n=84, 25)
    13.5 ± 19.4
    14.7 ± 25.6
        Appetite loss : C12/D1(n=76, 23)
    11 ± 21.4
    14.5 ± 24.3
        Appetite loss : C13/D1(n=74, 21)
    9.5 ± 20.3
    17.5 ± 27.1
        Appetite loss : C15/D1(n=62, 16)
    8.6 ± 20.9
    12.5 ± 26.9
        Appetite loss : C16/D1(n=53, 12)
    8.8 ± 18.7
    16.7 ± 30.2
        Appetite loss : C17/D1(n=47, 11)
    8.5 ± 16.3
    15.2 ± 31.1
        Appetite loss : C18/D1(n=45, 11)
    11.1 ± 17.4
    12.1 ± 22.5
        Appetite loss : C19/D1(n=40, 9)
    8.3 ± 16.5
    18.5 ± 33.8
        Appetite loss : C20/D1(n=35, 8)
    7.6 ± 16.3
    20.8 ± 35.4
        Appetite loss : C21/D1(n=30, 8)
    11.1 ± 16
    25 ± 34.5
        Appetite loss : C22/D1(n=24, 7)
    6.9 ± 13.8
    14.3 ± 37.8
        Appetite loss : C23/D1(n=23, 4)
    9.4 ± 14.9
    50 ± 43
        Appetite loss : C24/D1(n=20, 3)
    5 ± 12.2
    33.3 ± 33.3
        Appetite loss : C25/D1(n=18, 3)
    1.9 ± 7.9
    44.4 ± 50.9
        Appetite loss : C26/D1(n=14, 3)
    11.9 ± 21.1
    33.3 ± 33.3
        Appetite loss : C27/D1(n=14, 2)
    7.1 ± 19.3
    33.3 ± 47.1
        Appetite loss : C28/D1(n=11, 2)
    15.2 ± 17.4
    33.3 ± 47.1
        Appetite loss : C29/D1(n=8, 2)
    12.5 ± 17.3
    33.3 ± 47.1
        Appetite loss : C30/D1(n=8, 1)
    8.3 ± 15.4
    100 ± 0
        Appetite loss : C31/D1(n=7, 0)
    14.3 ± 17.8
    0 ± 0
        Constipation: Baseline (n=164, 162)
    14.8 ± 25.1
    16.9 ± 25
        Constipation: C2D1 (n=155, 133)
    28.6 ± 30.5
    14 ± 24.3
        Constipation: C3D1 (n=154, 106)
    27.1 ± 30
    16 ± 22.2
        Constipation: C4D1 (n=134, 90)
    22.9 ± 26.6
    14.8 ± 25.5
        Constipation: C5D1 (n=123, 74)
    21.4 ± 25.7
    20.3 ± 29.6
        Constipation: C6D1 (n=120, 70)
    21.7 ± 23.9
    15.7 ± 23.2
        Constipation: C7D1 (n=115, 52)
    21.7 ± 26.1
    19.9 ± 26.6
        Constipation: C8D1 (n=111, 43)
    18.6 ± 24.1
    16.3 ± 24.5
        Constipation: C9D1 (n=101, 37)
    18.8 ± 22.3
    16.2 ± 21.7
        Constipation: C10D1 (n=94, 33)
    16 ± 22.8
    19.2 ± 25
        Constipation: C11D1 (n=84, 25)
    21 ± 25.8
    21.3 ± 19
        Constipation: C12D1 (n=76, 23)
    19.7 ± 24.5
    21.7 ± 23.8
        Constipation: C13D1 (n=74, 21)
    21.2 ± 26.2
    22.2 ± 26.5
        Constipation: C14D1 (n=66, 19)
    21.7 ± 27.1
    24.6 ± 31.1
        Constipation: C15D1 (n=62, 16)
    22.6 ± 27.5
    18.7 ± 21
        Constipation: C16D1 (n=53, 12)
    19.5 ± 26.5
    22.2 ± 25.9
        Constipation: C17D1 (n=47, 11)
    22 ± 27.2
    24.2 ± 30.2
        Constipation: C18D1 (n=44, 11)
    22.7 ± 25.7
    15.2 ± 22.9
        Constipation: C19D1 (n=40, 9)
    25 ± 25.9
    22.2 ± 23.6
        Constipation: C20D1 (n=35, 8)
    22.9 ± 26.5
    20.8 ± 24.8
        Constipation: C21D1 (n=30, 8)
    24.4 ± 28.9
    16.7 ± 25.2
        Constipation: C22D1 (n=24, 7)
    18.1 ± 24
    19 ± 26.2
        Constipation: C23D1 (n=23, 4)
    11.6 ± 19.1
    25 ± 31.9
        Constipation: C24D1 (n=20, 3)
    21.7 ± 24.8
    22.2 ± 19.2
        Constipation: C25D1 (n=18, 3)
    22.2 ± 32.3
    33.3 ± 33.3
        Constipation: C26D1 (n=14, 3)
    26.2 ± 32.5
    44.4 ± 50.9
        Constipation: C27D1 (n=14, 2)
    35.7 ± 40.2
    50 ± 23.6
        Constipation: C28D1 (n=11, 2)
    21.2 ± 16.8
    50 ± 23.6
        Constipation: C29D1 (n=8, 2)
    29.2 ± 21.4
    50 ± 23.6
        Constipation: C30D1 (n=8, 1)
    29.2 ± 27.8
    33.3 ± 0
        Constipation: C31D1 (n=7, 0)
    33.3 ± 27.2
    0 ± 0
        Constipation: C32D1 (n=6, 0)
    33.3 ± 42.2
    0 ± 0
        Constipation: C33D1 (n=6, 0)
    38.9 ± 25.1
    0 ± 0
        Constipation: C34D1 (n=5, 0)
    40 ± 43.5
    0 ± 0
        Constipation: C35D1 (n=4, 0)
    33.3 ± 27.2
    0 ± 0
        Constipation: C36D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Constipation: C37D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Constipation: EOT (n=49, 90)
    28.6 ± 27.2
    18.1 ± 25.6
        Diarrhea: Baseline (n=165, 162)
    9.7 ± 19.1
    7.8 ± 16
        Diarrhea: C2D1 (n=155, 132)
    18.1 ± 26.7
    11.1 ± 20.5
        Diarrhea: C3D1 (n=153, 106)
    21.6 ± 28.7
    7.9 ± 18.1
        Diarrhea: C4D1 (n=134, 90)
    23.1 ± 26.9
    8.5 ± 18.4
        Diarrhea: C5D1 (n=123, 74)
    24.4 ± 25.6
    5.9 ± 15
        Diarrhea: C6D1 (n=120, 70)
    22.2 ± 26.4
    7.1 ± 16.9
        Diarrhea: C7D1 (n=115, 52)
    20.6 ± 24.8
    9.6 ± 16.6
        Diarrhea: C8D1 (n=111, 43)
    18.6 ± 24.1
    9.3 ± 19.7
        Diarrhea: C9D1 (n=101, 37)
    17.3 ± 22.8
    7.2 ± 16
        Diarrhea: C10D1 (n=94, 33)
    17.7 ± 22.3
    7.1 ± 16.2
        Diarrhea: C11D1 (n=84, 25)
    21 ± 22.4
    8 ± 17.4
        Diarrhea: C12D1 (n=76, 23)
    17.5 ± 25.2
    8.7 ± 15
        Diarrhea: C13D1 (n=74, 21)
    17.6 ± 23.6
    12.7 ± 19.7
        Diarrhea: C14D1 (n=66, 19)
    17.7 ± 22.8
    8.8 ± 18.7
        Diarrhea: C15D1 (n=62, 16)
    16.1 ± 21.5
    4.2 ± 11.4
        Diarrhea: C16D1 (n=52, 12)
    16 ± 20.3
    5.6 ± 13
        Diarrhea: C17D1 (n=47, 11)
    19.9 ± 22.7
    12.1 ± 22.5
        Diarrhea: C18D1 (n=44, 11)
    22.7 ± 25.7
    12.1 ± 22.5
        Diarrhea: C19D1 (n=40, 9)
    21.7 ± 25.7
    7.4 ± 14.7
        Diarrhea: C20D1 (n=35, 8)
    21 ± 24.4
    4.2 ± 11.8
        Diarrhea: C21D1 (n=30, 8)
    22.2 ± 22
    8.3 ± 15.4
        Diarrhea: C22D1 (n=24, 7)
    23.6 ± 25
    11.9 ± 15.9
        Diarrhea: C23D1 (n=23, 4)
    15.9 ± 19.8
    25 ± 16.7
        Diarrhea: C24D1 (n=20, 3)
    21.7 ± 22.4
    11.1 ± 19.2
        Diarrhea: C25D1 (n=18, 3)
    20.4 ± 25.9
    22.2 ± 19.2
        Diarrhea: C26D1 (n=14, 3)
    19 ± 25.2
    11.1 ± 19.2
        Diarrhea: C27D1 (n=14, 2)
    23.8 ± 30.5
    16.7 ± 23.6
        Diarrhea: C28D1 (n=11, 2)
    15.2 ± 17.4
    16.7 ± 23.6
        Diarrhea: C29D1 (n=8, 2)
    20.8 ± 24.8
    16.7 ± 23.6
        Diarrhea: C30D1 (n=8, 1)
    12.5 ± 17.3
    0 ± 0
        Diarrhea: C31D1 (n=7, 0)
    14.3 ± 17.8
    0 ± 0
        Diarrhea: C32D1 (n=6, 0)
    11.1 ± 17.2
    0 ± 0
        Diarrhea: C33D1 (n=6, 0)
    11.1 ± 17.2
    0 ± 0
        Diarrhea: C34D1 (n=5, 0)
    6.7 ± 14.9
    0 ± 0
        Diarrhea: C35D1 (n=4, 0)
    16.7 ± 19.2
    0 ± 0
        Diarrhea: C36D1 (n=1, 0)
    33.3 ± 0
    0 ± 0
        Diarrhea: C37D1 (n=1, 0)
    33.3 ± 0
    0 ± 0
        Diarrhea: EOT (n=49, 90)
    18.4 ± 23.6
    10 ± 21.5
        Financial Difficulties: Baseline (n=165, 161)
    28.5 ± 33
    27.3 ± 30.7
        Financial Difficulties: C2D1 (n=155, 133)
    21.9 ± 27.2
    22.3 ± 28.9
        Financial Difficulties: C3D1 (n=154, 105)
    19 ± 26.6
    20.3 ± 27.9
        Financial Difficulties: C4D1 (n=135, 90)
    17.5 ± 26
    21.9 ± 26
        Financial Difficulties: C5D1 (n=123, 74)
    16.8 ± 25
    19.4 ± 23.4
        Financial Difficulties: C6D1 (n=120, 70)
    15.6 ± 24
    18.6 ± 25.1
        Financial Difficulties: C7D1 (n=115, 52)
    14.8 ± 21.3
    18.6 ± 25.9
        Financial Difficulties: C8D1 (n=111, 43)
    16.8 ± 25
    15.5 ± 23.4
        Financial Difficulties: C9D1 (n=101, 36)
    17.8 ± 26.1
    16.7 ± 23.2
        Financial Difficulties: C10D1 (n=94, 33)
    16.3 ± 26.2
    15.2 ± 23.7
        Financial Difficulties: C11D1 (n=84, 25)
    17.5 ± 25.1
    17.3 ± 21.8
        Financial Difficulties: C12D1 (n=76, 23)
    17.1 ± 24.6
    18.8 ± 28.1
        Financial Difficulties: C13D1 (n=74, 21)
    16.2 ± 24.2
    17.5 ± 27.1
        Financial Difficulties: C14D1 (n=66, 19)
    14.1 ± 20.3
    17.5 ± 32.1
        Financial Difficulties: C15D1 (n=62, 16)
    14 ± 23
    16.7 ± 27.2
        Financial Difficulties: C16D1 (n=53, 12)
    15.7 ± 25
    30.6 ± 36.1
        Financial Difficulties: C17D1 (n=47, 11)
    17.7 ± 29.4
    33.3 ± 36.5
        Financial Difficulties: C18D1 (n=44, 11)
    18.9 ± 30
    15.2 ± 31.1
        Financial Difficulties: C19D1 (n=40, 9)
    17.5 ± 31.1
    25.9 ± 32.4
        Financial Difficulties: C20D1 (n=35, 8)
    16.2 ± 27.3
    25 ± 34.5
        Financial Difficulties: C21D1 (n=30, 8)
    13.3 ± 27.1
    29.2 ± 33
        Financial Difficulties: C22D1 (n=24, 7)
    18.1 ± 31.1
    28.6 ± 35.6
        Financial Difficulties: C23D1 (n=23, 4)
    17.4 ± 31.6
    33.3 ± 47.1
        Financial Difficulties: C24D1 (n=20, 3)
    20 ± 33.2
    33.3 ± 57.7
        Financial Difficulties: C25D1 (n=18, 3)
    11.1 ± 16.2
    44.4 ± 50.9
        Financial Difficulties: C26D1 (n=14, 3)
    14.3 ± 17.1
    44.4 ± 50.9
        Financial Difficulties: C27D1 (n=14, 2)
    14.3 ± 17.1
    66.7 ± 47.1
        Financial Difficulties: C28D1 (n=11, 2)
    15.2 ± 22.9
    66.7 ± 47.1
        Financial Difficulties: C29D1 (n=8, 2)
    8.3 ± 15.4
    66.7 ± 47.1
        Financial Difficulties: C30D1 (n=8, 1)
    4.2 ± 11.8
    100 ± 0
        Financial Difficulties: C31D1 (n=7, 0)
    9.5 ± 16.3
    0 ± 0
        Financial Difficulties: C32D1 (n=6, 0)
    22.2 ± 27.2
    0 ± 0
        Financial Difficulties: C33D1 (n=6, 0)
    16.7 ± 27.9
    0 ± 0
        Financial Difficulties: C34D1 (n=5, 0)
    13.3 ± 18.3
    0 ± 0
        Financial Difficulties: C35D1 (n=4, 0)
    8.3 ± 16.7
    0 ± 0
        Financial Difficulties: C36D1 (n=1, 0)
    33.3 ± 0
    0 ± 0
        Financial Difficulties: C37D1 (n=1, 0)
    66.7 ± 0
    0 ± 0
        Financial Difficulties: EOT (n=49, 90)
    17 ± 27.3
    24.1 ± 30
        Appetite loss: C32D1 (n=6, 0)
    11.1 ± 17.2
    0 ± 0
        Appetite loss: C33D1 (n=6, 0)
    11.1 ± 17.2
    0 ± 0
        Appetite loss: C34D1 (n=5, 0)
    13.3 ± 18.3
    0 ± 0
        Appetite loss: C35D1 (n=4, 0)
    16.7 ± 19.2
    0 ± 0
        Appetite loss: C36D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Appetite loss: C37D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Appetite loss: EOT (n=49, 90)
    21.8 ± 26
    28.1 ± 30.4
        Global Qol: EOT (n=49, 90)
    56.1 ± 24.5
    46.4 ± 25.4
        Physical Functioning: EOT (n=49, 90)
    80.7 ± 23
    66.2 ± 27.7
        Role Functioning: EOT (n=49, 90)
    71.8 ± 27.7
    54.1 ± 34.7
        Emotional Functioning: EOT (n=49, 90)
    75.2 ± 25.1
    74.5 ± 25.2
        Cognitive Functioning: EOT (n=49, 90)
    83.7 ± 20.3
    80 ± 24
        Social Function: EOT (n=49, 90)
    78.2 ± 27.9
    59.4 ± 33.5
        Fatigue: EOT (n=49, 90)
    32 ± 28.2
    46.9 ± 26.9
        Nausea and Vomiting: EOT (n=49, 90)
    16.3 ± 22.9
    15.7 ± 20.4
        Pain: EOT (n=49, 90)
    23.8 ± 30.4
    33.7 ± 31.3
        Dyspnea: EOT (n=49, 90)
    23.8 ± 28.1
    40 ± 30.1
        Insomnia: EOT (n=49, 90)
    18.4 ± 24.6
    30.4 ± 27.7
    No statistical analyses for this end point

    Secondary: European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Supplement Module for Lung Cancer (EORTC QLQ-LC13)

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    End point title
    European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Supplement Module for Lung Cancer (EORTC QLQ-LC13)
    End point description
    QLQ-LC13 consisted of 13 questions relating to disease symptoms specific to lung cancer and treatment side effects typical of treatment with chemotherapy and radiotherapy. The 13 questions comprised 1 multi-item scale for dyspnea and 10 single-item symptoms and side effects (coughing, hemoptysis, sore mouth, dysphagia, peripheral neuropathy, alopecia, chest pain, arm pain, other pain, and medicine for pain). Recall period: past week; response range: 1 'Not at All' to 4 'Very Much'. Scores averaged, transformed to 0-100 scale; higher symptom score = greater degree of symptoms.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of each cycle until disease progression, end of treatment (up to 112 weeks)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    164
    162
    Units: units on a scale
    arithmetic mean (standard deviation)
        Dyspnea: Baseline (n=164, 162)
    27.2 ± 21.7
    26.9 ± 23.4
        Dyspnea: C2D1 (n=155, 132)
    17.6 ± 18.1
    28.6 ± 22.3
        Dyspnea: C3D1 (n=153, 106)
    17.9 ± 17.8
    28 ± 25.4
        Dyspnea: C4D1 (n=135, 91)
    16.2 ± 17.5
    27.5 ± 22.8
        Dyspnea: C5D1 (n=123, 74)
    16.9 ± 16.7
    24.8 ± 22.9
        Dyspnea: C6D1 (n=119, 70)
    15.2 ± 15.8
    25.2 ± 23
        Dyspnea: C7D1 (n=115, 52)
    15.6 ± 16.5
    24.4 ± 20.3
        Dyspnea: C8D1 (n=111, 43)
    14.7 ± 16
    22 ± 22.8
        Dyspnea: C9D1 (n=101, 37)
    13.9 ± 15.8
    19.5 ± 19
        Dyspnea: C10D1 (n=94, 33)
    15.4 ± 17
    21.5 ± 21
        Dyspnea: C11D1 (n=84, 25)
    15.1 ± 17.5
    20.4 ± 24.1
        Dyspnea: C12D1 (n=76, 23)
    13.7 ± 15.5
    22.7 ± 22.1
        Dyspnea: C13D1 (n=74, 21)
    12.8 ± 14
    26.5 ± 25.9
        Dyspnea: C14D1 (n=66, 19)
    14.8 ± 16.9
    26.3 ± 26.8
        Dyspnea: C15D1 (n=62, 16)
    13.2 ± 15.4
    22.9 ± 18.4
        Dyspnea: C16D1 (n=53, 12)
    12.6 ± 11.7
    22.2 ± 18.3
        Dyspnea: C17D1 (n=46, 11)
    12.3 ± 11.5
    30.3 ± 23.9
        Dyspnea: C18D1 (n=45, 11)
    14.1 ± 13.5
    26.3 ± 20.7
        Dyspnea: C19D1 (n=40, 9)
    14.4 ± 13.8
    23.5 ± 15.2
        Dyspnea: C20D1 (n=35, 8)
    13.7 ± 12.9
    34.7 ± 24.1
        Dyspnea: C21D1 (n=30, 8)
    12.6 ± 13
    25 ± 14.2
        Dyspnea: C22D1 (n=24, 7)
    10.6 ± 11.1
    27 ± 21.1
        Dyspnea: C23D1 (n=23, 4)
    13.8 ± 14.2
    52.8 ± 19
        Dyspnea: C24D1 (n=20, 3)
    14.4 ± 14.9
    48.1 ± 23.1
        Dyspnea: C25D1 (n=18, 3)
    15.4 ± 12.1
    40.7 ± 23.1
        Dyspnea: C26D1 (n=14, 3)
    14.3 ± 10.2
    44.4 ± 22.2
        Dyspnea: C27D1 (n=14, 2)
    15.1 ± 11.2
    55.6 ± 0
        Dyspnea: C28D1 (n=11, 2)
    11.1 ± 8.6
    61.1 ± 7.9
        Dyspnea: C29D1 (n=8, 2)
    12.5 ± 11
    50 ± 7.9
        Dyspnea: C30D1 (n=8, 1)
    9.7 ± 7.1
    77.8 ± 0
        Dyspnea: C31D1 (n=7, 0)
    15.9 ± 8.7
    0 ± 0
        Dyspnea: C32D1 (n=6, 0)
    18.5 ± 9.1
    0 ± 0
        Dyspnea: C33D1 (n=6, 0)
    18.5 ± 9.1
    0 ± 0
        Dyspnea: C34D1 (n=5, 0)
    20 ± 5
    0 ± 0
        Dyspnea: C35D1 (n=4, 0)
    16.7 ± 6.4
    0 ± 0
        Dyspnea: C36D1 (n=1, 0)
    22.2 ± 0
    0 ± 0
        Dyspnea: C37D1 (n=1, 0)
    11.1 ± 0
    0 ± 0
        Dyspnea: EOT (n=49, 90)
    21.8 ± 19
    35.6 ± 26.7
        Coughing: Baseline (n=164, 162)
    38.2 ± 27.4
    42.2 ± 31.3
        Coughing: C2D1 (n=155, 132)
    23 ± 19.6
    34.8 ± 26.3
        Coughing: C3D1 (n=153, 106)
    23.5 ± 21.6
    32.4 ± 27.4
        Coughing: C4D1 (n=135, 91)
    19.8 ± 22.4
    27.1 ± 24.8
        Coughing: C5D1 (n=123, 74)
    18.4 ± 21
    25.7 ± 25
        Coughing: C6D1 (n=119, 70)
    14.6 ± 18.2
    30 ± 25.5
        Coughing: C7D1 (n=115, 52)
    15.9 ± 18.4
    26.3 ± 23.2
        Coughing: C8D1 (n=111, 43)
    13.2 ± 18.7
    22.5 ± 23.8
        Coughing: C9D1 (n=101, 37)
    13.5 ± 18.4
    25.2 ± 28.8
        Coughing: C10D1 (n=94, 33)
    14.2 ± 19.2
    20.2 ± 26.3
        Coughing: C11D1 (n=83, 25)
    12.9 ± 20.7
    18.7 ± 25.6
        Coughing: C12D1 (n=76, 23)
    14.5 ± 20.6
    23.2 ± 25.5
        Coughing: C13D1 (n=74, 21)
    14 ± 21.4
    27 ± 27.1
        Coughing: C14D1 (n=66, 19)
    13.1 ± 19.3
    24.6 ± 31.1
        Coughing: C15D1 (n=62, 16)
    11.8 ± 21
    20.8 ± 20.6
        Coughing: C16D1 (n=53, 12)
    13.8 ± 19
    22.2 ± 21.7
        Coughing: C17D1 (n=47, 11)
    6.4 ± 15
    27.3 ± 25
        Coughing: C18D1 (n=45, 11)
    13.3 ± 18
    18.2 ± 17.4
        Coughing: C19D1 (n=40, 9)
    12.5 ± 18
    14.8 ± 17.6
        Coughing: C20D1 (n=35, 8)
    10.5 ± 15.7
    29.2 ± 21.4
        Coughing: C21D1 (n=30, 8)
    13.3 ± 24.1
    33.3 ± 25.2
        Coughing: C22D1 (n=24, 7)
    8.3 ± 14.7
    28.6 ± 23
        Coughing: C23D1 (n=23, 4)
    11.6 ± 19.1
    33.3 ± 0
        Coughing: C24D1 (n=20, 3)
    8.3 ± 14.8
    44.4 ± 19.2
        Coughing: C25D1 (n=18, 3)
    5.6 ± 12.8
    44.4 ± 19.2
        Coughing: C26D1 (n=14, 3)
    2.4 ± 8.9
    33.3 ± 0
        Coughing: C27D1 (n=14, 2)
    7.1 ± 14.2
    50 ± 23.6
        Coughing: C28D1 (n=11, 2)
    18.2 ± 31.1
    50 ± 23.6
        Coughing: C29D1 (n=8, 2)
    8.3 ± 15.4
    33.3 ± 0
        Coughing: C30D1 (n=8, 1)
    20.8 ± 24.8
    33.3 ± 0
        Coughing: C31D1 (n=7, 0)
    19 ± 17.8
    0 ± 0
        Coughing: C32D1 (n=6, 0)
    16.7 ± 27.9
    0 ± 0
        Coughing: C33D1 (n=6, 0)
    11.1 ± 17.2
    0 ± 0
        Coughing: C34D1 (n=5, 0)
    20 ± 29.8
    0 ± 0
        Coughing: C35D1 (n=4, 0)
    33.3 ± 47.1
    0 ± 0
        Coughing: C36D1 (n=1, 0)
    33.3 ± 0
    0 ± 0
        Coughing: C37D1 (n=1, 0)
    33.3 ± 0
    0 ± 0
        Coughing: EOT (n=49, 90)
    25.9 ± 23.8
    37.4 ± 29.1
        Hemoptysis: Baseline (n=164, 162)
    2.4 ± 9.5
    3.7 ± 12.3
        Hemoptysis: C2D1 (n=155, 132)
    1.7 ± 7.4
    3.5 ± 12.5
        Hemoptysis: C3D1 (n=153, 106)
    0.9 ± 5.3
    2.2 ± 8.3
        Hemoptysis: C4D1 (n=135, 91)
    1 ± 5.7
    1.5 ± 6.9
        Hemoptysis: C5D1 (n=123, 74)
    0.3 ± 3
    0.9 ± 5.4
        Hemoptysis: C6D1 (n=119, 70)
    0.6 ± 4.3
    3.8 ± 14.5
        Hemoptysis: C7D1 (n=115, 52)
    0 ± 0
    1.3 ± 9.2
        Hemoptysis: C8D1 (n=111, 43)
    0.9 ± 7
    2.3 ± 11.3
        Hemoptysis: C9D1 (n=101, 37)
    0.3 ± 3.3
    2.7 ± 12.1
        Hemoptysis: C10D1 (n=94, 33)
    0.4 ± 3.4
    3 ± 17.4
        Hemoptysis: C11D1 (n=83, 25)
    2.4 ± 11.4
    4 ± 14.7
        Hemoptysis: C12D1 (n=76, 23)
    0.9 ± 5.4
    5.8 ± 21.7
        Hemoptysis: C13D1 (n=74, 21)
    2.3 ± 10.1
    4.8 ± 15.9
        Hemoptysis: C14D1 (n=66, 19)
    0.5 ± 4.1
    0 ± 0
        Hemoptysis: C15D1 (n=62, 16)
    1.1 ± 5.9
    0 ± 0
        Hemoptysis: C16D1 (n=53, 12)
    0.6 ± 4.6
    5.6 ± 13
        Hemoptysis: C17D1 (n=47, 11)
    0 ± 0
    9.1 ± 21.6
        Hemoptysis: C18D1 (n=45, 11)
    1.5 ± 6.9
    3 ± 10.1
        Hemoptysis: C19D1 (n=40, 9)
    0 ± 0
    3.7 ± 11.1
        Hemoptysis: C20D1 (n=35, 8)
    1 ± 5.6
    8.3 ± 15.4
        Hemoptysis: C21D1 (n=30, 8)
    0 ± 0
    4.2 ± 11.8
        Hemoptysis: C22D1 (n=24, 7)
    0 ± 0
    9.5 ± 16.3
        Hemoptysis: C23D1 (n=23, 4)
    1.4 ± 7
    0 ± 0
        Hemoptysis: C24D1 (n=20, 3)
    0 ± 0
    0 ± 0
        Hemoptysis: C25D1 (n=18, 3)
    0 ± 0
    0 ± 0
        Hemoptysis: C26D1 (n=14, 3)
    0 ± 0
    0 ± 0
        Hemoptysis: C27D1 (n=14, 2)
    0 ± 0
    0 ± 0
        Hemoptysis: C28D1 (n=11, 2)
    0 ± 0
    0 ± 0
        Hemoptysis: C29D1 (n=8, 2)
    0 ± 0
    0 ± 0
        Hemoptysis: C30D1 (n=8, 1)
    0 ± 0
    0 ± 0
        Hemoptysis: C31D1 (n=7, 0)
    0 ± 0
    0 ± 0
        Hemoptysis: C32D1 (n=6, 0)
    0 ± 0
    0 ± 0
        Hemoptysis: C33D1 (n=6, 0)
    0 ± 0
    0 ± 0
        Hemoptysis: C34D1 (n=5, 0)
    0 ± 0
    0 ± 0
        Hemoptysis: C35D1 (n=4, 0)
    0 ± 0
    0 ± 0
        Hemoptysis: C36D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Hemoptysis: C37D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Hemoptysis: EOT (n=49, 90)
    0.7 ± 4.8
    4.8 ± 13.7
        Sore Mouth: Baseline (n=164, 162)
    5.5 ± 15.3
    6.4 ± 18.4
        Sore Mouth: C2D1 (n=155, 132)
    8 ± 17.9
    9.1 ± 18.5
        Sore Mouth: C3D1 (n=153, 106)
    7 ± 14.6
    9.4 ± 21
        Sore Mouth: C4D1 (n=135, 91)
    8.1 ± 16.5
    10.3 ± 21.5
        Sore Mouth: C5D1 (n=123, 73)
    5.1 ± 12.1
    9.6 ± 20.4
        Sore Mouth: C6D1 (n=119, 70)
    4.8 ± 13.9
    10.5 ± 19.3
        Sore Mouth: C7D1 (n=115, 52)
    5.2 ± 15
    7.7 ± 15.6
        Sore Mouth: C8D1 (n=111, 43)
    3 ± 9.6
    10.9 ± 18.9
        Sore Mouth: C9D1 (n=101, 37)
    4.8 ± 12.5
    10.8 ± 22.3
        Sore Mouth: C10D1 (n=94, 33)
    6.4 ± 14.9
    12.1 ± 23.3
        Sore Mouth: C11D1 (n=84, 25)
    4.8 ± 14.8
    9.3 ± 18.1
        Sore Mouth: C12D1 (n=76, 23)
    3.9 ± 12.1
    8.7 ± 18
        Sore Mouth: C13D1 (n=74, 21)
    4.5 ± 12.7
    9.5 ± 15.4
        Sore Mouth: C14D1 (n=66, 19)
    4.5 ± 12.9
    7 ± 14
        Sore Mouth: C15D1 (n=62, 16)
    5.4 ± 12.4
    14.6 ± 29.7
        Sore Mouth: C16D1 (n=53, 12)
    6.3 ± 14.7
    8.3 ± 15.1
        Sore Mouth: C17D1 (n=47, 11)
    3.5 ± 10.4
    6.1 ± 13.5
        Sore Mouth: C18D1 (n=45, 11)
    5.2 ± 12.2
    12.1 ± 16.8
        Sore Mouth: C19D1 (n=40, 9)
    4.2 ± 11.2
    7.4 ± 14.7
        Sore Mouth: C20D1 (n=35, 8)
    7.6 ± 16.3
    12.5 ± 24.8
        Sore Mouth: C21D1 (n=30, 8)
    4.4 ± 11.5
    4.2 ± 11.8
        Sore Mouth: C22D1 (n=24, 7)
    5.6 ± 12.7
    7.1 ± 13.1
        Sore Mouth: C23D1 (n=23, 4)
    5.1 ± 11.7
    16.7 ± 19.2
        Sore Mouth: C24D1 (n=20, 3)
    6.7 ± 17.4
    0 ± 0
        Sore Mouth: C25D1 (n=18, 3)
    0 ± 0
    0 ± 0
        Sore Mouth: C26D1 (n=14, 3)
    4.8 ± 17.8
    11.1 ± 19.2
        Sore Mouth: C27D1 (n=14, 2)
    7.1 ± 19.3
    16.7 ± 23.6
        Sore Mouth: C28D1 (n=11, 2)
    6.1 ± 20.1
    0 ± 0
        Sore Mouth: C29D1 (n=8, 2)
    8.3 ± 15.4
    16.7 ± 23.6
        Sore Mouth: C30D1 (n=8, 1)
    8.3 ± 23.6
    0 ± 0
        Sore Mouth: C31D1 (n=7, 0)
    9.5 ± 25.2
    0 ± 0
        Sore Mouth: C32D1 (n=6, 0)
    0 ± 0
    0 ± 0
        Sore Mouth: C33D1 (n=6, 0)
    0 ± 0
    0 ± 0
        Sore Mouth: C34D1 (n=5, 0)
    0 ± 0
    0 ± 0
        Sore Mouth: C35D1 (n=4, 0)
    0 ± 0
    0 ± 0
        Sore Mouth: C36D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Sore Mouth: C37D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Sore Mouth: EOT (n=49, 90)
    3.4 ± 10.2
    8.1 ± 18.2
        Dysphagia: Baseline (n=164, 162)
    7.1 ± 16.4
    8.6 ± 20.9
        Dysphagia: C2D1 (n=155, 132)
    8.2 ± 15.4
    9.8 ± 19.2
        Dysphagia: C3D1 (n=153, 106)
    7.6 ± 16.4
    9.7 ± 20.6
        Dysphagia: C4D1 (n=135, 91)
    6.2 ± 15.3
    8.1 ± 19.5
        Dysphagia: C5D1 (n=123, 74)
    6 ± 14.8
    7.7 ± 17
        Dysphagia: C6D1 (n=119, 70)
    7 ± 15
    10 ± 16.4
        Dysphagia: C7D1 (n=115, 52)
    4.1 ± 11.8
    5.1 ± 13.8
        Dysphagia: C8D1 (n=111, 43)
    3.2 ± 11.1
    6.2 ± 15
        Dysphagia: C9D1 (n=101, 37)
    5 ± 11.9
    7.2 ± 16
        Dysphagia: C10D1 (n=94, 33)
    4.3 ± 12.2
    6.1 ± 13.1
        Dysphagia: C11D1 (n=84, 25)
    3.2 ± 9.8
    4 ± 11.1
        Dysphagia: C12D1 (n=76, 23)
    3.5 ± 10.3
    7.2 ± 17.3
        Dysphagia: C13D1 (n=74, 21)
    4.1 ± 11
    6.3 ± 13.4
        Dysphagia: C14D1 (n=66, 19)
    3 ± 11.3
    7 ± 14
        Dysphagia: C15D1 (n=62, 16)
    3.8 ± 13.6
    4.2 ± 16.7
        Dysphagia: C16D1 (n=53, 12)
    4.4 ± 11.4
    2.8 ± 9.6
        Dysphagia: C17D1 (n=47, 11)
    2.8 ± 9.4
    6.1 ± 13.5
        Dysphagia: C18D1 (n=45, 11)
    3.7 ± 10.6
    3 ± 10.1
        Dysphagia: C19D1 (n=40, 9)
    4.2 ± 11.2
    0 ± 0
        Dysphagia: C20D1 (n=35, 8)
    4.8 ± 14.3
    8.3 ± 15.4
        Dysphagia: C21D1 (n=30, 8)
    3.3 ± 10.2
    8.3 ± 15.4
        Dysphagia: C22D1 (n=24, 7)
    2.8 ± 9.4
    0 ± 0
        Dysphagia: C23D1 (n=23, 4)
    2.9 ± 9.6
    8.3 ± 16.7
        Dysphagia: C24D1 (n=20, 3)
    5 ± 22.4
    0 ± 0
        Dysphagia: C25D1 (n=18, 3)
    0 ± 0
    11.1 ± 19.2
        Dysphagia: C26D1 (n=14, 3)
    9.5 ± 27.5
    11.1 ± 19.2
        Dysphagia: C27D1 (n=14, 2)
    2.4 ± 8.9
    16.7 ± 23.6
        Dysphagia: C28D1 (n=11, 2)
    6.1 ± 13.5
    16.7 ± 23.6
        Dysphagia: C29D1 (n=8, 2)
    8.3 ± 15.4
    16.7 ± 23.6
        Dysphagia: C30D1 (n=8, 1)
    0 ± 0
    33.3 ± 0
        Dysphagia: C31D1 (n=7, 0)
    4.8 ± 12.6
    0 ± 0
        Dysphagia: C32D1 (n=6, 0)
    5.6 ± 13.6
    0 ± 0
        Dysphagia: C33D1 (n=6, 0)
    0 ± 0
    0 ± 0
        Dysphagia: C34D1 (n=5, 0)
    6.7 ± 14.9
    0 ± 0
        Dysphagia: C35D1 (n=4, 0)
    8.3 ± 16.7
    0 ± 0
        Dysphagia: C36D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Dysphagia: C37D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Dysphagia: EOT (n=49, 90)
    4.8 ± 13.6
    8.5 ± 19.7
        Peripheral Neuropathy: Baseline (n=164, 162)
    14 ± 22.1
    17.7 ± 27.3
        Peripheral Neuropathy: C2D1 (n=155, 132)
    18.1 ± 24.1
    21.5 ± 29.2
        Peripheral Neuropathy: C3D1 (n=153, 106)
    17.6 ± 26.2
    18.2 ± 29.1
        Peripheral Neuropathy: C4D1 (n=134, 91)
    15.9 ± 23
    21.6 ± 27.8
        Peripheral Neuropathy: C5D1 (n=123, 74)
    15.2 ± 21
    21.2 ± 28.4
        Peripheral Neuropathy: C6D1 (n=119, 70)
    13.7 ± 21.9
    18.1 ± 27
        Peripheral Neuropathy: C7D1 (n=115, 52)
    13 ± 21
    21.8 ± 28.7
        Peripheral Neuropathy: C8D1 (n=111, 43)
    10.8 ± 20.2
    24 ± 32.8
        Peripheral Neuropathy: C9D1 (n=101, 37)
    11.2 ± 19.6
    29.7 ± 34.1
        Peripheral Neuropathy: C10D1 (n=94, 33)
    11.3 ± 21.1
    27.3 ± 29.4
        Peripheral Neuropathy: C11D1 (n=84, 25)
    11.1 ± 21.5
    24 ± 31.2
        Peripheral Neuropathy: C12D1 (n=76, 23)
    11.4 ± 22.1
    33.3 ± 36.2
        Peripheral Neuropathy: C13D1 (n=74, 21)
    10.4 ± 19.1
    33.3 ± 35
        Peripheral Neuropathy: C14D1 (n=66, 19)
    10.6 ± 21.2
    29.8 ± 35
        Peripheral Neuropathy: C15D1 (n=62, 16)
    8.6 ± 18
    25 ± 31
        Peripheral Neuropathy: C16D1 (n=52, 12)
    10.3 ± 19.3
    25 ± 20.7
        Peripheral Neuropathy: C17D1 (n=47, 11)
    12.1 ± 23.5
    27.3 ± 29.1
        Peripheral Neuropathy: C18D1 (n=45, 11)
    11.9 ± 22.6
    30.3 ± 31.5
        Peripheral Neuropathy: C19D1 (n=40, 9)
    9.2 ± 20
    22.2 ± 16.7
        Peripheral Neuropathy: C20D1 (n=35, 8)
    12.4 ± 25.7
    33.3 ± 30.9
        Peripheral Neuropathy: C21D1 (n=30, 8)
    11.1 ± 18.2
    29.2 ± 21.4
        Peripheral Neuropathy: C22D1 (n=24, 7)
    8.3 ± 20.3
    28.6 ± 23
        Peripheral Neuropathy: C23D1 (n=23, 4)
    8.7 ± 20.6
    41.7 ± 31.9
        Peripheral Neuropathy: C24D1 (n=20, 3)
    3.3 ± 14.9
    44.4 ± 38.5
        Peripheral Neuropathy: C25D1 (n=18, 3)
    9.3 ± 19.2
    44.4 ± 38.5
        Peripheral Neuropathy: C26D1 (n=14, 3)
    16.7 ± 36.4
    22.2 ± 19.2
        Peripheral Neuropathy: C27D1 (n=14, 2)
    9.5 ± 20.4
    66.7 ± 0
        Peripheral Neuropathy: C28D1 (n=11, 2)
    15.2 ± 22.9
    33.3 ± 0
        Peripheral Neuropathy: C29D1 (n=8, 2)
    12.5 ± 24.8
    50 ± 23.6
        Peripheral Neuropathy: C30D1 (n=8, 1)
    16.7 ± 30.9
    33.3 ± 0
        Peripheral Neuropathy: C31D1 (n=7, 0)
    19 ± 32.5
    0 ± 0
        Peripheral Neuropathy: C32D1 (n=6, 0)
    11.1 ± 27.2
    0 ± 0
        Peripheral Neuropathy: C33D1 (n=6, 0)
    11.1 ± 27.2
    0 ± 0
        Peripheral Neuropathy: C34D1 (n=5, 0)
    20 ± 44.7
    0 ± 0
        Peripheral Neuropathy: C35D1 (n=4, 0)
    25 ± 50
    0 ± 0
        Peripheral Neuropathy: C36D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Peripheral Neuropathy: C37D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Peripheral Neuropathy: EOT (n=49, 90)
    10.2 ± 16.9
    21.9 ± 29.6
        Alopecia: Baseline (n=163, 162)
    17.4 ± 30.6
    16.9 ± 29.8
        Alopecia: C2D1 (n=155, 132)
    9.5 ± 21.4
    36.6 ± 39.7
        Alopecia: C3D1 (n=153, 106)
    7.6 ± 18.1
    30.5 ± 36.5
        Alopecia: C4D1 (n=135, 91)
    8.9 ± 22
    24.9 ± 32
        Alopecia: C5D1 (n=123, 74)
    6 ± 17.1
    23.9 ± 31
        Alopecia: C6D1 (n=118, 70)
    4.2 ± 14.8
    23.3 ± 32.8
        Alopecia: C7D1 (n=115, 52)
    4.9 ± 14.1
    19.9 ± 30.4
        Alopecia: C8D1 (n=111, 43)
    3.9 ± 11.7
    18.6 ± 28.5
        Alopecia: C9D1 (n=101, 37)
    4 ± 11.8
    16.2 ± 23.1
        Alopecia: C10D1 (n=94, 33)
    4.6 ± 14.3
    14.1 ± 22.1
        Alopecia: C11D1 (n=84, 25)
    4 ± 15
    16 ± 21.8
        Alopecia: C12D1 (n=76, 23)
    4.4 ± 14.7
    20.3 ± 26.1
        Alopecia: C13D1 (n=74, 21)
    6.3 ± 18
    12.7 ± 19.7
        Alopecia: C14D1 (n=65, 19)
    3.6 ± 14.6
    15.8 ± 23.2
        Alopecia: C15D1 (n=62, 16)
    4.8 ± 16.9
    8.3 ± 19.2
        Alopecia: C16D1 (n=53, 12)
    6.3 ± 18.6
    13.9 ± 22.3
        Alopecia: C17D1 (n=46, 11)
    5.1 ± 17.2
    18.2 ± 22.9
        Alopecia: C18D1 (n=45, 11)
    3.7 ± 12.8
    18.2 ± 22.9
        Alopecia: C19D1 (n=40, 9)
    5.8 ± 19.8
    18.5 ± 24.2
        Alopecia: C20D1 (n=35, 8)
    3.8 ± 13.5
    25 ± 23.6
        Alopecia: C21D1 (n=30, 8)
    7.8 ± 22.6
    16.7 ± 25.2
        Alopecia: C22D1 (n=24, 7)
    2.8 ± 9.4
    14.3 ± 17.8
        Alopecia: C23D1 (n=23, 3)
    1.4 ± 7
    22.2 ± 19.2
        Alopecia: C24D1 (n=20, 3)
    6.7 ± 23.2
    33.3 ± 33.3
        Alopecia: C25D1 (n=18, 3)
    9.3 ± 27.5
    33.3 ± 33.3
        Alopecia: C26D1 (n=14, 3)
    7.1 ± 26.7
    44.4 ± 38.5
        Alopecia: C27D1 (n=14, 2)
    16.7 ± 36.4
    33.3 ± 0
        Alopecia: C28D1 (n=11, 2)
    6.1 ± 20.1
    50 ± 23.6
        Alopecia: C29D1 (n=8, 2)
    16.7 ± 35.6
    33.3 ± 0
        Alopecia: C30D1 (n=8, 1)
    12.5 ± 35.4
    33.3 ± 0
        Alopecia: C31D1 (n=7, 0)
    9.5 ± 25.2
    0 ± 0
        Alopecia: C32D1 (n=6, 0)
    0 ± 0
    0 ± 0
        Alopecia: C33D1 (n=6, 0)
    0 ± 0
    0 ± 0
        Alopecia: C34D1 (n=5, 0)
    0 ± 0
    0 ± 0
        Alopecia: C35D1 (n=4, 0)
    0 ± 0
    0 ± 0
        Alopecia: C36D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Alopecia: C37D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Alopecia: EOT (n=49, 90)
    6.8 ± 18
    33.3 ± 37.7
        Pain in Chest: Baseline (n=163, 160)
    18.8 ± 22.8
    24 ± 27.5
        Pain in Chest: C2D1 (n=155, 132)
    9.5 ± 17.7
    23.7 ± 25.9
        Pain in Chest: C3D1 (n=153, 106)
    7 ± 13.6
    23.3 ± 26.5
        Pain in Chest: C4D1 (n=135, 91)
    7.4 ± 13.9
    19.8 ± 22.8
        Pain in Chest: C5D1 (n=123, 74)
    6.8 ± 14.1
    17.1 ± 21.5
        Pain in Chest: C6D1 (n=119, 70)
    6.2 ± 13
    16.2 ± 22.5
        Pain in Chest: C7D1 (n=115, 52)
    7.5 ± 14.7
    16.7 ± 22.4
        Pain in Chest: C8D1 (n=111, 43)
    5.1 ± 14.4
    14 ± 20.9
        Pain in Chest: C9D1 (n=101, 37)
    5.9 ± 12.8
    17.1 ± 23.1
        Pain in Chest: C10D1 (n=94, 33)
    6.7 ± 14.3
    18.2 ± 31.3
        Pain in Chest: C11D1 (n=84, 25)
    6.3 ± 13.2
    20 ± 25.5
        Pain in Chest: C12D1 (n=76, 23)
    5.3 ± 12.2
    23.2 ± 30.9
        Pain in Chest: C13D1 (n=74, 21)
    6.3 ± 13.1
    23.8 ± 30.1
        Pain in Chest: C14D1 (n=66, 19)
    7.6 ± 16.3
    22.8 ± 22.4
        Pain in Chest: C15D1 (n=62, 16)
    5.9 ± 14.2
    18.7 ± 24.2
        Pain in Chest: C16D1 (n=53, 12)
    3.8 ± 10.7
    16.7 ± 17.4
        Pain in Chest: C17D1 (n=46, 11)
    7.2 ± 15.6
    21.2 ± 22.5
        Pain in Chest: C18D1 (n=45, 11)
    5.9 ± 16.3
    24.2 ± 33.6
        Pain in Chest: C19D1 (n=40, 9)
    5 ± 14.2
    18.5 ± 24.2
        Pain in Chest: C20D1 (n=35, 8)
    5.7 ± 15.1
    29.2 ± 21.4
        Pain in Chest: C21D1 (n=30, 8)
    5.6 ± 15.4
    25 ± 23.6
        Pain in Chest: C22D1 (n=24, 7)
    4.2 ± 11.3
    26.2 ± 30.2
        Pain in Chest: C23D1 (n=23, 4)
    3.6 ± 10
    41.7 ± 31.9
        Pain in Chest: C24D1 (n=20, 3)
    1.7 ± 7.5
    33.3 ± 33.3
        Pain in Chest: C25D1 (n=18, 3)
    5.6 ± 12.8
    33.3 ± 33.3
        Pain in Chest: C26D1 (n=14, 3)
    7.1 ± 19.3
    33.3 ± 33.3
        Pain in Chest: C27D1 (n=14, 2)
    4.8 ± 12.1
    50 ± 23.6
        Pain in Chest: C28D1 (n=11, 2)
    9.1 ± 15.6
    50 ± 23.6
        Pain in Chest: C29D1 (n=8, 2)
    0 ± 0
    50 ± 23.6
        Pain in Chest: C30D1 (n=8, 1)
    4.2 ± 11.8
    66.7 ± 0
        Pain in Chest: C31D1 (n=7, 0)
    9.5 ± 16.3
    0 ± 0
        Pain in Chest: C32D1 (n=6, 0)
    0 ± 0
    0 ± 0
        Pain in Chest: C33D1 (n=6, 0)
    0 ± 0
    0 ± 0
        Pain in Chest: C34D1 (n=5, 0)
    6.7 ± 14.9
    0 ± 0
        Pain in Chest: C35D1 (n=4, 0)
    8.3 ± 16.7
    0 ± 0
        Pain in Chest: C36D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Pain in Chest: C37D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Pain in Chest: EOT (n=49, 90)
    17 ± 24.6
    28.5 ± 29.4
        Pain in Arm or Shoulder: Baseline (n=164, 161)
    16.3 ± 24.1
    19.5 ± 28
        Pain in Arm or Shoulder: C2D1 (n=155, 132)
    9 ± 18.3
    19.9 ± 27
        Pain in Arm or Shoulder: C3D1 (n=153, 105)
    8.1 ± 14.8
    17.5 ± 24.5
        Pain in Arm or Shoulder: C4D1 (n=135, 91)
    6.9 ± 15.3
    14.3 ± 22.3
        Pain in Arm or Shoulder: C5D1 (n=123, 74)
    6.2 ± 15
    13.1 ± 21.9
        Pain in Arm or Shoulder: C6D1 (n=119, 70)
    6.7 ± 14.1
    17.1 ± 25.8
        Pain in Arm or Shoulder: C7D1 (n=115, 52)
    6.4 ± 13.2
    17.3 ± 23.3
        Pain in Arm or Shoulder: C8D1 (n=111, 43)
    6.9 ± 14.3
    20.2 ± 28.3
        Pain in Arm or Shoulder: C9D1 (n=101, 37)
    5.6 ± 12.5
    23.4 ± 28.2
        Pain in Arm or Shoulder: C10D1 (n=94, 33)
    7.4 ± 17
    25.3 ± 32.3
        Pain in Arm or Shoulder: C11D1 (n=84, 25)
    6 ± 14.8
    24 ± 26.4
        Pain in Arm or Shoulder: C12D1 (n=76, 23)
    6.6 ± 15.4
    29 ± 35.3
        Pain in Arm or Shoulder: C13D1 (n=74, 21)
    5.9 ± 12.8
    25.4 ± 34.8
        Pain in Arm or Shoulder: C14D1 (n=66, 19)
    7.6 ± 18.3
    29.8 ± 31.2
        Pain in Arm or Shoulder: C15D1 (n=62, 16)
    5.4 ± 13.8
    25 ± 25.8
        Pain in Arm or Shoulder: C16D1 (n=53, 12)
    5 ± 12
    16.7 ± 22.5
        Pain in Arm or Shoulder: C17D1 (n=47, 11)
    3.5 ± 10.4
    21.2 ± 22.5
        Pain in Arm or Shoulder: C18D1 (n=45, 11)
    8.1 ± 20.3
    30.3 ± 34.8
        Pain in Arm or Shoulder: C19D1 (n=40, 9)
    6.7 ± 15.5
    18.5 ± 24.2
        Pain in Arm or Shoulder: C20D1 (n=35, 8)
    9.5 ± 22.2
    25 ± 23.6
        Pain in Arm or Shoulder: C21D1 (n=30, 8)
    7.8 ± 16.8
    29.2 ± 27.8
        Pain in Arm or Shoulder: C22D1 (n=24, 7)
    2.8 ± 9.4
    21.4 ± 24.9
        Pain in Arm or Shoulder: C23D1 (n=23, 4)
    0.7 ± 3.5
    33.3 ± 38.5
        Pain in Arm or Shoulder: C24D1 (n=20, 3)
    3.3 ± 10.3
    44.4 ± 38.5
        Pain in Arm or Shoulder: C25D1 (n=18, 3)
    1.9 ± 7.9
    33.3 ± 33.3
        Pain in Arm or Shoulder: C26D1 (n=14, 3)
    7.1 ± 19.3
    22.2 ± 19.2
        Pain in Arm or Shoulder: C27D1 (n=14, 2)
    4.8 ± 12.1
    50 ± 23.6
        Pain in Arm or Shoulder: C28D1 (n=11, 2)
    0 ± 0
    33.3 ± 0
        Pain in Arm or Shoulder: C29D1 (n=8, 2)
    0 ± 0
    66.7 ± 0
        Pain in Arm or Shoulder: C30D1 (n=8, 1)
    0 ± 0
    33.3 ± 0
        Pain in Arm or Shoulder: C31D1 (n=7, 0)
    0 ± 0
    0 ± 0
        Pain in Arm or Shoulder: C32D1 (n=6, 0)
    11.1 ± 17.2
    0 ± 0
        Pain in Arm or Shoulder: C33D1 (n=6, 0)
    0 ± 0
    0 ± 0
        Pain in Arm or Shoulder: C34D1 (n=5, 0)
    0 ± 0
    0 ± 0
        Pain in Arm or Shoulder: C35D1 (n=4, 0)
    0 ± 0
    0 ± 0
        Pain in Arm or Shoulder: C36D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Pain in Arm or Shoulder: C37D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Pain in Arm or Shoulder: EOT (n=48, 90)
    11.1 ± 21
    21.9 ± 28.8
        Pain in Other Parts: Baseline (n=163, 158)
    23.1 ± 27.3
    31.4 ± 30.4
        Pain in Other Parts: C2D1 (n=153, 125)
    15 ± 23.2
    25.9 ± 28
        Pain in Other Parts: C3D1 (n=152, 104)
    11.4 ± 20.7
    21.2 ± 27.1
        Pain in Other Parts: C4D1 (n=134, 90)
    12.7 ± 22.7
    21.5 ± 24.6
        Pain in Other Parts: C5D1 (n=123, 73)
    14.4 ± 23
    20.5 ± 27.6
        Pain in Other Parts: C6D1 (n=118, 68)
    10.7 ± 18.9
    18.1 ± 26
        Pain in Other Parts: C7D1 (n=115, 51)
    11.3 ± 20.7
    16.3 ± 26.1
        Pain in Other Parts: C8D1 (n=111, 42)
    10.5 ± 20.6
    22.2 ± 30.9
        Pain in Other Parts: C9D1 (n=100, 37)
    10.7 ± 21.1
    24.3 ± 31.1
        Pain in Other Parts: C10D1 (n=92, 33)
    9.8 ± 18.8
    28.3 ± 35.5
        Pain in Other Parts: C11D1 (n=83, 25)
    12.4 ± 21.3
    24 ± 29.7
        Pain in Other Parts: C12D1 (n=74, 23)
    12.2 ± 20.3
    24.6 ± 30.5
        Pain in Other Parts: C13D1 (n=74, 21)
    10.8 ± 19.2
    31.7 ± 34.1
        Pain in Other Parts: C14D1 (n=66, 19)
    11.6 ± 18
    24.6 ± 29.1
        Pain in Other Parts: C15D1 (n=61, 16)
    9.8 ± 15.3
    25 ± 22.8
        Pain in Other Parts: C16D1 (n=53, 12)
    10.7 ± 19.4
    38.9 ± 34.3
        Pain in Other Parts: C17D1 (n=46, 11)
    13.8 ± 19.3
    24.2 ± 21.6
        Pain in Other Parts: C18D1 (n=45, 11)
    10.4 ± 19.9
    33.3 ± 39.4
        Pain in Other Parts: C19D1 (n=40, 9)
    14.2 ± 22.5
    25.9 ± 14.7
        Pain in Other Parts: C20D1 (n=35, 8)
    13.3 ± 20.1
    29.2 ± 21.4
        Pain in Other Parts: C21D1 (n=30, 8)
    21.1 ± 27
    29.2 ± 37.5
        Pain in Other Parts: C22D1 (n=24, 7)
    12.5 ± 21.6
    40.5 ± 30.2
        Pain in Other Parts: C23D1 (n=23, 4)
    5.1 ± 11.7
    41.7 ± 31.9
        Pain in Other Parts: C24D1 (n=20, 3)
    6.7 ± 17.4
    11.1 ± 19.2
        Pain in Other Parts: C25D1 (n=18, 3)
    9.3 ± 15.4
    44.4 ± 38.5
        Pain in Other Parts: C26D1 (n=14, 3)
    23.8 ± 30.5
    33.3 ± 33.3
        Pain in Other Parts: C27D1 (n=14, 2)
    16.7 ± 31.4
    50 ± 23.6
        Pain in Other Parts: C28D1 (n=11, 2)
    6.1 ± 13.5
    33.3 ± 0
        Pain in Other Parts: C29D1 (n=8, 2)
    4.2 ± 11.8
    16.7 ± 23.6
        Pain in Other Parts: C30D1 (n=8, 1)
    12.5 ± 17.3
    33.3 ± 0
        Pain in Other Parts: C31D1 (n=7, 0)
    9.5 ± 16.3
    0 ± 0
        Pain in Other Parts: C32D1 (n=6, 0)
    5.6 ± 13.6
    0 ± 0
        Pain in Other Parts: C33D1 (n=6, 0)
    0 ± 0
    0 ± 0
        Pain in Other Parts: C34D1 (n=5, 0)
    6.7 ± 14.9
    0 ± 0
        Pain in Other Parts: C35D1 (n=4, 0)
    0 ± 0
    0 ± 0
        Pain in Other Parts: C36D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Pain in Other Parts: C37D1 (n=1, 0)
    0 ± 0
    0 ± 0
        Pain in Other Parts: EOT (n=49, 90)
    18.4 ± 29.7
    29.6 ± 34.8
    No statistical analyses for this end point

    Secondary: European Quality of Life - 5 Dimensional (EQ-5D) Visual Analog Scale (VAS)

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    End point title
    European Quality of Life - 5 Dimensional (EQ-5D) Visual Analog Scale (VAS)
    End point description
    EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 1 of each cycle until disease progression, end of treatment (up to 112 weeks)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    164
    161
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n=164, 161)
    64.09 ± 21.04
    66.76 ± 20.74
        C2D1 (n=153, 131)
    69.19 ± 19.42
    66.33 ± 20.3
        C3D1 (n=153, 105)
    73.13 ± 18.97
    65.84 ± 20.8
        C4D1 (n=135, 90)
    73.78 ± 18.25
    69.13 ± 18.14
        C5D1 (n=122, 74)
    75.27 ± 17.99
    68.12 ± 23.19
        C6D1 (n=120, 70)
    75.79 ± 18.67
    69.71 ± 22.46
        C7D1 (n=115, 52)
    77.02 ± 17.34
    70.63 ± 24.31
        C8D1 (n=110, 43)
    74.72 ± 18.09
    72.3 ± 23.54
        C9D1 (n=101, 37)
    74.45 ± 18.32
    72.27 ± 25.85
        C10D1 (n=94, 33)
    75.49 ± 18.18
    74.27 ± 24.88
        C11D1 (n=84, 25)
    76.32 ± 17
    77.24 ± 20.31
        C12D1 (n=77, 23)
    76.95 ± 17.63
    74.83 ± 22.6
        C13D1 (n=73, 21)
    76.38 ± 17.5
    73 ± 23.54
        C14D1 (n=66, 19)
    78.77 ± 15.54
    74.11 ± 22.56
        C15D1 (n=62, 16)
    77.71 ± 16.78
    77.44 ± 19.52
        C16D1 (n=53, 12)
    75.32 ± 16.21
    79 ± 13.28
        C17D1 (n=47, 11)
    75.09 ± 17.68
    81.73 ± 15.98
        C18D1 (n=45, 11)
    75.87 ± 16.63
    78.91 ± 16.25
        C19D1 (n=40, 9)
    76.85 ± 16.39
    78 ± 14.04
        C20D1 (n=35, 8)
    72.66 ± 19.81
    76.75 ± 17.65
        C21D1 (n=30, 8)
    74.13 ± 16.19
    73.63 ± 19.41
        C22D1 (n=24, 7)
    77.54 ± 17.54
    72.21 ± 19.79
        C23D1 (n=23, 4)
    75.48 ± 17.75
    54 ± 16.35
        C24D1 (n=20, 3)
    71.4 ± 23.15
    62 ± 20.3
        C25D1 (n=18, 3)
    75.61 ± 15.97
    63.67 ± 22.59
        C26D1 (n=14, 3)
    72.14 ± 20.71
    63 ± 17.52
        C27D1 (n=14, 2)
    66.57 ± 16.96
    50 ± 14.14
        C28D1 (n=11, 2)
    72.36 ± 12.72
    55 ± 21.21
        C29D1 (n=8, 2)
    71.38 ± 12.28
    45 ± 14.14
        C30D1 (n=8, 1)
    69.5 ± 17
    40 ± 0
        C31D1 (n=7, 0)
    68.57 ± 16.76
    0 ± 0
        C32D1 (n=6, 0)
    65.83 ± 19.41
    0 ± 0
        C33D1 (n=6, 0)
    67.5 ± 20.34
    0 ± 0
        C34D1 (n=5, 0)
    68 ± 20.8
    0 ± 0
        C35D1 (n=4, 0)
    72.25 ± 14.84
    0 ± 0
        C36D1 (n=1, 0)
    90 ± 0
    0 ± 0
        C37D1 (n=1, 0)
    85 ± 0
    0 ± 0
        EOT (n=49, 90)
    68.33 ± 21.25
    58.34 ± 23.71
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Active reporting period is from the time of informed consent until at least 28 days after the last dose of study treatment.
    Adverse event reporting additional description
    All causality (serious and non-serious) AEs have been reported. Non-serious AEs above the 5% threshold are reported herein. All causality deaths include deaths not related to the trial. Deaths resulting from AEs include all deaths considered to be causally related to AEs. All information are taken from the safety database.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Chemotherapy
    Reporting group description
    Pemetrexed 500 mg/m^2 intravenous infusion over 10 minutes or docetaxel 75 mg/m^2 intravenous infusion over 1 hour on Day 1 of 21-day cycle, as per investigator discretion. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred.

    Reporting group title
    Crizotinib
    Reporting group description
    Crizotinib (PF-02341066) 250 mg (administered as two 100-mg tablets and one 50-mg tablet) orally twice daily continuously in 21-day cycles. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent occurred.

    Serious adverse events
    Chemotherapy Crizotinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 171 (24.56%)
    80 / 172 (46.51%)
         number of deaths (all causes)
    7
    30
         number of deaths resulting from adverse events
    1
    3
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 171 (1.17%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cancer surgery
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour haemorrhage
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer recurrent
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (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
    Product contamination microbial
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    2 / 171 (1.17%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 171 (0.00%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Disease progression
         subjects affected / exposed
    3 / 171 (1.75%)
    18 / 172 (10.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 18
         deaths causally related to treatment / all
    0 / 3
    0 / 16
    Fatigue
         subjects affected / exposed
    1 / 171 (0.58%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    2 / 171 (1.17%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 171 (0.58%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    General physical health deterioration
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 171 (0.58%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 171 (0.00%)
    3 / 172 (1.74%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 171 (0.00%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    2 / 171 (1.17%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Cardiac arrest
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 171 (0.58%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 171 (1.17%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 171 (1.17%)
    6 / 172 (3.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Interstitial lung disease
         subjects affected / exposed
    0 / 171 (0.00%)
    3 / 172 (1.74%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Organising pneumonia
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 171 (1.75%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary artery thrombosis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 171 (1.75%)
    7 / 172 (4.07%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 171 (1.17%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    12 / 171 (7.02%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    15 / 15
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 171 (1.17%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 171 (1.17%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 171 (0.00%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral cyst
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 171 (0.58%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 171 (1.17%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 171 (0.00%)
    3 / 172 (1.74%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal cyst
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hepatitis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 171 (1.17%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 171 (0.58%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 171 (0.58%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Empyema
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 171 (1.17%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 171 (0.00%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 171 (0.58%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 171 (1.75%)
    8 / 172 (4.65%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia bacterial
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 171 (0.58%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    1 / 171 (0.58%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 171 (0.00%)
    2 / 172 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    0 / 171 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Chemotherapy Crizotinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    169 / 171 (98.83%)
    172 / 172 (100.00%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    32 / 171 (18.71%)
    31 / 172 (18.02%)
         occurrences all number
    38
    78
    Chest pain
         subjects affected / exposed
    13 / 171 (7.60%)
    15 / 172 (8.72%)
         occurrences all number
    17
    18
    Fatigue
         subjects affected / exposed
    60 / 171 (35.09%)
    51 / 172 (29.65%)
         occurrences all number
    106
    83
    Oedema
         subjects affected / exposed
    6 / 171 (3.51%)
    15 / 172 (8.72%)
         occurrences all number
    6
    25
    Pyrexia
         subjects affected / exposed
    33 / 171 (19.30%)
    41 / 172 (23.84%)
         occurrences all number
    43
    51
    Oedema peripheral
         subjects affected / exposed
    15 / 171 (8.77%)
    59 / 172 (34.30%)
         occurrences all number
    16
    105
    Pain
         subjects affected / exposed
    9 / 171 (5.26%)
    10 / 172 (5.81%)
         occurrences all number
    10
    11
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    13 / 171 (7.60%)
    19 / 172 (11.05%)
         occurrences all number
    14
    21
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    3 / 171 (1.75%)
    11 / 172 (6.40%)
         occurrences all number
    3
    15
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    21 / 171 (12.28%)
    72 / 172 (41.86%)
         occurrences all number
    36
    195
    Aspartate aminotransferase increased
         subjects affected / exposed
    17 / 171 (9.94%)
    55 / 172 (31.98%)
         occurrences all number
    25
    127
    Blood alkaline phosphatase increased
         subjects affected / exposed
    6 / 171 (3.51%)
    18 / 172 (10.47%)
         occurrences all number
    8
    27
    Neutrophil count decreased
         subjects affected / exposed
    9 / 171 (5.26%)
    15 / 172 (8.72%)
         occurrences all number
    11
    73
    Blood creatinine increased
         subjects affected / exposed
    3 / 171 (1.75%)
    13 / 172 (7.56%)
         occurrences all number
    3
    27
    Weight decreased
         subjects affected / exposed
    8 / 171 (4.68%)
    21 / 172 (12.21%)
         occurrences all number
    9
    29
    White blood cell count decreased
         subjects affected / exposed
    13 / 171 (7.60%)
    16 / 172 (9.30%)
         occurrences all number
    15
    66
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 171 (0.00%)
    9 / 172 (5.23%)
         occurrences all number
    0
    20
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 171 (0.00%)
    9 / 172 (5.23%)
         occurrences all number
    0
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    27 / 171 (15.79%)
    36 / 172 (20.93%)
         occurrences all number
    46
    81
    Leukopenia
         subjects affected / exposed
    9 / 171 (5.26%)
    24 / 172 (13.95%)
         occurrences all number
    16
    110
    Neutropenia
         subjects affected / exposed
    18 / 171 (10.53%)
    41 / 172 (23.84%)
         occurrences all number
    28
    222
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    35 / 171 (20.47%)
    37 / 172 (21.51%)
         occurrences all number
    42
    56
    Dyspnoea
         subjects affected / exposed
    29 / 171 (16.96%)
    27 / 172 (15.70%)
         occurrences all number
    43
    39
    Epistaxis
         subjects affected / exposed
    10 / 171 (5.85%)
    3 / 172 (1.74%)
         occurrences all number
    11
    3
    Haemoptysis
         subjects affected / exposed
    11 / 171 (6.43%)
    9 / 172 (5.23%)
         occurrences all number
    12
    10
    Oropharyngeal pain
         subjects affected / exposed
    7 / 171 (4.09%)
    20 / 172 (11.63%)
         occurrences all number
    10
    24
    Rhinorrhoea
         subjects affected / exposed
    9 / 171 (5.26%)
    4 / 172 (2.33%)
         occurrences all number
    10
    5
    Productive cough
         subjects affected / exposed
    8 / 171 (4.68%)
    12 / 172 (6.98%)
         occurrences all number
    10
    15
    Pulmonary embolism
         subjects affected / exposed
    2 / 171 (1.17%)
    9 / 172 (5.23%)
         occurrences all number
    2
    10
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    17 / 171 (9.94%)
    45 / 172 (26.16%)
         occurrences all number
    20
    66
    Dizziness
         subjects affected / exposed
    13 / 171 (7.60%)
    34 / 172 (19.77%)
         occurrences all number
    15
    49
    Headache
         subjects affected / exposed
    26 / 171 (15.20%)
    46 / 172 (26.74%)
         occurrences all number
    29
    85
    Neuropathy peripheral
         subjects affected / exposed
    10 / 171 (5.85%)
    5 / 172 (2.91%)
         occurrences all number
    10
    7
    Paraesthesia
         subjects affected / exposed
    7 / 171 (4.09%)
    13 / 172 (7.56%)
         occurrences all number
    10
    18
    Peripheral sensory neuropathy
         subjects affected / exposed
    6 / 171 (3.51%)
    9 / 172 (5.23%)
         occurrences all number
    9
    12
    Visual perseveration
         subjects affected / exposed
    0 / 171 (0.00%)
    12 / 172 (6.98%)
         occurrences all number
    0
    18
    Eye disorders
    Photopsia
         subjects affected / exposed
    1 / 171 (0.58%)
    21 / 172 (12.21%)
         occurrences all number
    2
    27
    Vision blurred
         subjects affected / exposed
    5 / 171 (2.92%)
    13 / 172 (7.56%)
         occurrences all number
    7
    19
    Visual impairment
         subjects affected / exposed
    8 / 171 (4.68%)
    74 / 172 (43.02%)
         occurrences all number
    8
    106
    Lacrimation increased
         subjects affected / exposed
    9 / 171 (5.26%)
    1 / 172 (0.58%)
         occurrences all number
    10
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 171 (4.68%)
    18 / 172 (10.47%)
         occurrences all number
    9
    22
    Abdominal pain upper
         subjects affected / exposed
    13 / 171 (7.60%)
    17 / 172 (9.88%)
         occurrences all number
    13
    17
    Constipation
         subjects affected / exposed
    39 / 171 (22.81%)
    83 / 172 (48.26%)
         occurrences all number
    61
    150
    Diarrhoea
         subjects affected / exposed
    34 / 171 (19.88%)
    106 / 172 (61.63%)
         occurrences all number
    44
    332
    Dyspepsia
         subjects affected / exposed
    6 / 171 (3.51%)
    18 / 172 (10.47%)
         occurrences all number
    9
    22
    Nausea
         subjects affected / exposed
    60 / 171 (35.09%)
    104 / 172 (60.47%)
         occurrences all number
    125
    249
    Stomatitis
         subjects affected / exposed
    13 / 171 (7.60%)
    9 / 172 (5.23%)
         occurrences all number
    16
    16
    Vomiting
         subjects affected / exposed
    32 / 171 (18.71%)
    88 / 172 (51.16%)
         occurrences all number
    51
    311
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 171 (0.00%)
    12 / 172 (6.98%)
         occurrences all number
    0
    14
    Dysphagia
         subjects affected / exposed
    2 / 171 (1.17%)
    9 / 172 (5.23%)
         occurrences all number
    2
    11
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    35 / 171 (20.47%)
    21 / 172 (12.21%)
         occurrences all number
    39
    26
    Dry skin
         subjects affected / exposed
    2 / 171 (1.17%)
    10 / 172 (5.81%)
         occurrences all number
    2
    13
    Pruritus
         subjects affected / exposed
    7 / 171 (4.09%)
    12 / 172 (6.98%)
         occurrences all number
    7
    17
    Rash
         subjects affected / exposed
    30 / 171 (17.54%)
    23 / 172 (13.37%)
         occurrences all number
    36
    34
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    20 / 171 (11.70%)
    15 / 172 (8.72%)
         occurrences all number
    36
    16
    Back pain
         subjects affected / exposed
    11 / 171 (6.43%)
    30 / 172 (17.44%)
         occurrences all number
    12
    37
    Musculoskeletal pain
         subjects affected / exposed
    6 / 171 (3.51%)
    14 / 172 (8.14%)
         occurrences all number
    6
    18
    Myalgia
         subjects affected / exposed
    19 / 171 (11.11%)
    5 / 172 (2.91%)
         occurrences all number
    25
    6
    Pain in extremity
         subjects affected / exposed
    10 / 171 (5.85%)
    20 / 172 (11.63%)
         occurrences all number
    12
    28
    Muscle spasms
         subjects affected / exposed
    4 / 171 (2.34%)
    9 / 172 (5.23%)
         occurrences all number
    4
    10
    Neck pain
         subjects affected / exposed
    5 / 171 (2.92%)
    11 / 172 (6.40%)
         occurrences all number
    5
    12
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    46 / 171 (26.90%)
    56 / 172 (32.56%)
         occurrences all number
    67
    151
    Hyperglycaemia
         subjects affected / exposed
    9 / 171 (5.26%)
    12 / 172 (6.98%)
         occurrences all number
    13
    26
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 171 (0.58%)
    16 / 172 (9.30%)
         occurrences all number
    1
    34
    Hypokalaemia
         subjects affected / exposed
    5 / 171 (2.92%)
    15 / 172 (8.72%)
         occurrences all number
    5
    24
    Hypocalcaemia
         subjects affected / exposed
    0 / 171 (0.00%)
    13 / 172 (7.56%)
         occurrences all number
    0
    23
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 171 (8.19%)
    24 / 172 (13.95%)
         occurrences all number
    18
    33
    Nasopharyngitis
         subjects affected / exposed
    7 / 171 (4.09%)
    32 / 172 (18.60%)
         occurrences all number
    10
    63

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Aug 2009
    Protocol was updated based on feedback from a Special Protocol Assessment completed by the Federal Drug Administration (FDA). Specific changes were to central laboratory requirements for ALK testing; entry criteria modifications; survival analysis modifications; PK requirements were updated; sample size for ECG substudy and independent radiology review requirements were modified.
    23 Nov 2009
    RECIST version 1.0 changed to version 1.1; CTCAE criteria changed from version 3.0 to version 4.0; primary endpoint changed from ORR to PFS, interim analysis timelines were updated; randomization block design updated; survival follow up period revised; tumor assessments were updated to be based on calendar and not cycle; toxicity management for pemetrexed and docetaxel updated; wound healing timelines was added; administration for PF 02341066 was updated to be with or without food; dose modification section for PF 02341066 updated based on safety database.
    21 Dec 2009
    Japan specific amendment: Modifications were made for Japanese sites only regarding eligibility criteria.
    26 Jan 2010
    Update to pemetrexed dosing administration and contraception requirements based on approved packet insert.
    18 Feb 2010
    France specific amendment: Modifications were made for French sites only to require all patients in France to have both MUGA scans (or echocardiograms) and ophthalmology examinations at scheduled times during the study.
    08 Mar 2010
    Ireland specific amendment: Modifications were made for Ireland sites only to require all patients for Irish sites to have a MUGA test at scheduled times during the study
    22 Jun 2010
    The patient reported VSAQ ALK was included, additional ECG monitoring was added for patients with QTc >500 msec, modifications of the eligibility criteria (which included cutoffs for hemoglobin and platelet counts) were included, washout period for cardiovascular (CV) or cerebrovascular events was decreased, hypertension exclusion criteria was deleted, all available scans required review by a third party radiology laboratory, a treatment delay to up to 42 days without requiring discontinuation was allowed; and metabolites of crizotinib were evaluated, if possible
    05 Aug 2010
    Additional safety monitoring for the potential AEs of pneumonitis were added and an exclusion criterion to exclude patients with known interstitial fibrosis or interstitial lung disease was added.
    12 Jan 2011
    Dose modifications for crizotinib updated; dose administration guidelines for docetaxel and pemetrexed updated; safety guidelines for potential cases of drug induced liver injury added; washout for palliative radiation changed.
    09 Nov 2011
    Sample size requirement was updated after planned interim analysis removed and study design assumptions revised post consultation and approval by the US FDA. Time to tumor response was added as a secondary endpoint. Duration of survival evaluation period was extended. Revised monitoring guidance for Hy’s Law and new safety and monitoring guidance for complex renal cysts development was added. Language was added regarding the Internal Oncology Business Unit Safety Data Monitoring Committee. Text modified in some sections to ensure compliance with the Sponsor protocol template.
    21 Mar 2012
    France specific amendment: Modifications were made for French sites only: safety information about Hy’s Law cases provided and dose modification rules were revised for patients with drug-related ALT increases.
    31 Dec 2012
    Modifications based on the country specific amendment for France regarding updated safety information about Hy's Law cases and such. A reduced schedule of assessments for ongoing patients in Arm A was provided. The total number of OS events required to conduct the final OS analysis was revised. Detailed description of patients of child bearing potential language as an inclusion criteria and detailed contraception guidelines were introduced to ensure consistency with updated Sponsor protocol. Text was added or replaced to ensure consistency with updated Pfizer protocol template language especially regarding medication error, and SAE reporting for Oncology studies after the active safety reporting period was clarified. Use of prophylactic antiemetics and concomitant acetaminophen/paracetamol was clarified. Prohibited medications use by topical administration was added. Pregnancy testing in response to IRBs/IECs and/or local regulations was clarified. Reporting of local cardiologist manual ECG overread was clarified. Corrections of typographical errors/omissions and other administrative inconsistencies were made throughout the protocol.
    03 Dec 2014
    Blood sample collection for hematology and blood chemistries will now be during non visit cycles. Survival follow up data collection text clarified to be collected until the required number of Overall Survival events has been reached or until death, whichever is earlier. Reduced Schedule of Activities was introduced for patients still ongoing after Secondary Overall Survival endpoint is reached. Dose modification and adverse event management guidance were revised for bradycardia and pneumonitis, based on the updated safety information. Some text was revised to ensure consistency with updated Sponsor protocol template language especially regarding contraception guidelines, pregnancy testing, and serious adverse event reporting for Oncology studies after permanent discontinuation of study treatment. Corrections of typographical errors and other administrative inconsistencies were made throughout the protocol.

    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.
    No analyses of ALK fusion variants or protein expression were done due to limited slide stability of unstained tissue sections required for immunohistochemistry and no nucleic acid based assay was available to identify specific ALK gene fusion.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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