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    Clinical Trial Results:
    A Phase 3, Randomized, Open-Label Study of the Efficacy and Safety of Crizotinib Versus Pemetrexed/Cisplatin or Pemetrexed/Carboplatin in Previously Untreated Subjects With Non-Squamous Carcinoma of the Lung Harboring a Translocation or Inversion Event Involving the Anaplastic Lymphoma Kinase (ALK) Gene Locus.

    Summary
    EudraCT number
    2010-021336-33
    Trial protocol
    DE   ES   FI   IE   AT   IT   GB   BE   NL   DK   PT   NO  
    Global end of trial date
    30 Nov 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Oct 2017
    First version publication date
    14 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A8081014
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01154140
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 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
    16 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that crizotinib (Arm A) is superior to first-line chemotherapy, pemetrexed/cisplatin or pemetrexed/carboplatin (Arm B), in prolonging progression free survival in subjects with advanced non-small cell lung cancer (NSCLC) whose tumors harbor a translocation or inversion event involving the ALK gene locus.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Jan 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    72 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 25
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Brazil: 6
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    China: 39
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Hong Kong: 3
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Italy: 36
    Country: Number of subjects enrolled
    Japan: 32
    Country: Number of subjects enrolled
    Korea, Republic of: 55
    Country: Number of subjects enrolled
    Luxembourg: 2
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Russian Federation: 10
    Country: Number of subjects enrolled
    Singapore: 14
    Country: Number of subjects enrolled
    South Africa: 1
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    Ukraine: 6
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 28
    Worldwide total number of subjects
    343
    EEA total number of subjects
    107
    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)
    288
    From 65 to 84 years
    55
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subjects with histologically or cytologically proven diagnosis of locally advanced, recurrent, or metastatic non squamous NSCLC and tumors with measurable disease were enrolled. Subjects were to be positive for translocation or inversion events involving the ALK gene locus as determined by an ALK break apart Fluorescence In-Situ Hybridization test.

    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 250 milligram (mg) capsule, orally twice daily was administered in treatment cycle of 21 days. Subjects could continue crizotinib treatment beyond the time of Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 defined progressive disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the subject was perceived to be experiencing clinical benefit.
    Arm type
    Experimental

    Investigational medicinal product name
    Crizotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Crizotinib 250 mg capsule administered orally twice daily in cycles of 21 days.

    Arm title
    Chemotherapy
    Arm description
    Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 intravenous (IV) infusion according to standard of care was administered over 10 minutes (min); either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an area under the concentration time curve (AUC) of 5 or 6 milligram*minute per millilitre (mg*min/mL), approximately 30 min after end of pemetrexed infusion.
    Arm type
    Active comparator

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pemetrexed 500 mg/m^2 IV infusion administered over 10 min according to standard of care.

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin IV infusion administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL over 30 min according to standard of care.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 75 mg/m^2 IV infusion administered over 30 min according to standard of care.

    Number of subjects in period 1
    Crizotinib Chemotherapy
    Started
    172
    171
    Treated
    171
    169
    Completed
    81
    69
    Not completed
    91
    102
         Randomized,not treated
    1
    2
         Adverse event, serious fatal
    71
    81
         Unspecified
    3
    1
         Consent withdrawn by subject
    12
    13
         Lost to follow-up
    4
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Crizotinib
    Reporting group description
    Crizotinib 250 milligram (mg) capsule, orally twice daily was administered in treatment cycle of 21 days. Subjects could continue crizotinib treatment beyond the time of Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 defined progressive disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the subject was perceived to be experiencing clinical benefit.

    Reporting group title
    Chemotherapy
    Reporting group description
    Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 intravenous (IV) infusion according to standard of care was administered over 10 minutes (min); either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an area under the concentration time curve (AUC) of 5 or 6 milligram*minute per millilitre (mg*min/mL), approximately 30 min after end of pemetrexed infusion.

    Reporting group values
    Crizotinib Chemotherapy Total
    Number of subjects
    172 171 343
    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)
    149 139 288
        From 65-84 years
    23 32 55
        85 years and over
    0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    50.9 ± 11.9 52.9 ± 13.1 -
    Gender, Male/Female
    Units: Subjects
        Female
    104 108 212
        Male
    68 63 131

    End points

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    End points reporting groups
    Reporting group title
    Crizotinib
    Reporting group description
    Crizotinib 250 milligram (mg) capsule, orally twice daily was administered in treatment cycle of 21 days. Subjects could continue crizotinib treatment beyond the time of Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 defined progressive disease (PD), as determined by independent radiology review (IRR), at the discretion of the investigator if the subject was perceived to be experiencing clinical benefit.

    Reporting group title
    Chemotherapy
    Reporting group description
    Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously on Day 1 of each cycle for a maximum of 6 cycles. Pemetrexed 500 mg per meter square (m)^2 intravenous (IV) infusion according to standard of care was administered over 10 minutes (min); either cisplatin 75 mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion or carboplatin was administered at a dose calculated to produce an area under the concentration time curve (AUC) of 5 or 6 milligram*minute per millilitre (mg*min/mL), approximately 30 min after end of pemetrexed infusion.

    Primary: Progression-Free Survival (PFS) Based on IRR

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    End point title
    Progression-Free Survival (PFS) Based on IRR
    End point description
    PFS was defined as the time from the date of randomization in study until the date of first documented objective tumor progression (according to RECIST v1.1 as determined by IRR) or death (due to any cause), whichever occurred first. PFS was calculated as (first event date − randomization date +1)/30.44. Objective progression was defined as a 20 percent (%) increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 millimeter (mm) or clear progression of pre-existing non-target lesions or the appearance of any new clear lesions. Full Analysis (FA)= subjects who were randomized with study treatment assignment designated according to the initial randomization.
    End point type
    Primary
    End point timeframe
    Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    172
    171
    Units: months
        median (confidence interval 95%)
    10.9 (8.3 to 13.9)
    7 (6.8 to 8.2)
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    343
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001 [1]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.454
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.346
         upper limit
    0.596
    Notes
    [1] - P-value was obtained from 1-sided log rank test, stratified by eastern cooperative oncology group performance status (ECOG PS),race,brain metastases. 1-sided log-rank test at 0.0247 level of significance was used to compare PFS between the 2 arms.

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS (in months) was defined as the duration from start of study treatment to date of death due to any cause. OS =(date of death minus the date of randomization of study medication plus 1) divided by 30.4. For subjects who were alive, overall survival was censored on last date the subjects were known to be alive. FA population included all subjects who were randomized with study treatment assignment designated according to the initial randomization.
    End point type
    Secondary
    End point timeframe
    From randomization to death or last date known alive for those not known to have died (up to 72 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    172
    171
    Units: months
        median (confidence interval 95%)
    99999 (45.8 to 99999)
    47.5 (32.2 to 99999)
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    343
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0489 [2]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.548
         upper limit
    1.053
    Notes
    [2] - P-value was obtained from 1-sided log rank test, stratified by ECOG PS, race group and brain metastases.

    Secondary: Overall Survival Probability at Month 12 and 18

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    End point title
    Overall Survival Probability at Month 12 and 18
    End point description
    Overall survival probability at Month 12 and 18 was defined as the probability of overall survival at 12 and 18 months respectively, where the OS was defined as the duration from start of study treatment to date of death due to any cause. The survival probability was estimated using the Kaplan-Meier method. FA population included all subjects who were randomized with study treatment assignment designated according to the initial randomization.
    End point type
    Secondary
    End point timeframe
    Month 12, 18
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    172
    171
    Units: percent probability
    number (confidence interval 95%)
        Month 12
    83.5 (77 to 88.3)
    78.4 (71.3 to 83.9)
        Month 18
    71.5 (64 to 77.7)
    66.6 (58.8 to 73.2)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR): Percentage of Subjects With Objective Response as Assessed by IRR

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    End point title
    Objective Response Rate (ORR): Percentage of Subjects With Objective Response as Assessed by IRR
    End point description
    ORR was defined as percentage of subjects with complete response (CR) or partial response (PR) according to RECIST v1.1 determined by IRR. CR was defined as complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis less than [<] 10 mm). No new lesions and disappearance of all non-target lesions. PR was defined as greater than or equal to (>=) 30% decrease taking as reference the baseline sum of lesion dimensions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No clear progression of non-target disease. No new lesions. FA population included all subjects who were randomized with study treatment assignment designated according to the initial randomization.
    End point type
    Secondary
    End point timeframe
    Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    172
    171
    Units: percentage of subjects
        number (confidence interval 95%)
    74.4 (67.2 to 80.8)
    45 (37.4 to 52.8)
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    If the PFS endpoint was significant, ORR was to be considered significant if the 2-sided p-value from Pearson chi-square test was (less than or equal to)<= 0.0494.
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    343
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001 [3]
    Method
    Pearson chi-square test
    Parameter type
    Difference in percentage
    Point estimate
    29.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    19.5
         upper limit
    39.3
    Notes
    [3] - P-value was obtained from a Pearson chi-square test

    Secondary: Duration of Response (DR) Based on IRR

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    End point title
    Duration of Response (DR) Based on IRR
    End point description
    Time from first documentation of objective tumor response(CR or PR)to first documentation of PD or death due to any cause,whichever occurred first as per RECISTv1.1 determined by IRR.CR:complete disappearance of all target and non-target disease.All nodes(target, non-target)must decrease to normal(short axis <10 mm).No new lesions,disappearance of all non-target lesions.PR:>=30% decrease taking as reference the baseline sum of lesion dimensions.Short axis was used in sum for target nodes,while longest diameter was used in sum for all or target lesions.No clear progression of non-target disease.c)PD:20 % increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study(includes the baseline sum if that is the smallest on study)with a minimum absolute increase of 5 mm or clear progression of pre-existing non-target lesions or the appearance of any new clear lesions.FA set.N=subjects with objective tumor response evaluable for the endpoint.
    End point type
    Secondary
    End point timeframe
    From objective response to date of progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    128
    77
    Units: weeks
        median (confidence interval 95%)
    49 (35.1 to 60)
    22.9 (18 to 25.1)
    No statistical analyses for this end point

    Secondary: Time to tumor response (TTR) Based on IRR

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    End point title
    Time to tumor response (TTR) Based on IRR
    End point description
    TTR was defined as the time from randomization to first documentation of objective tumor response (CR or PR) according to RECIST v1.1 determined by IRR. CR: complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR: >=30% decrease taking as reference the baseline sum of lesion dimensions. Short axis was used in sum for target nodes, while longest diameter was used in sum for all or target lesions. No clear progression of non-target disease. No new lesions. FA population included all subjects who were randomized with study treatment assignment designated according to the initial randomization. Here "N" signifies subjects with objective tumor response and were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Randomization to first documentation of objective tumor response (up to 35 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    128
    77
    Units: weeks
        median (full range (min-max))
    6.1 (2.7 to 41.4)
    12.1 (5.1 to 36.7)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Disease Control at Week 12 Based on IRR

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    End point title
    Percentage of Subjects With Disease Control at Week 12 Based on IRR
    End point description
    Disease control rate at week 12 is defined as the percent of subjects with CR, PR, or stable disease (SD) at week 12 according to RECIST v1.1 determined by IRR. The best response of SD would be assigned if SD criteria was met at least once after randomization at a minimum interval of 6 weeks. CR: complete disappearance of all target lesions and non-target disease, with exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis <10 mm). No new lesions and disappearance of all non-target lesions. PR: >=30% decrease taking as reference the baseline sum of lesion dimensions. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters. Short axis was used in sum for target nodes, while longest diameter was used in sum for all or target lesions. No clear progression of non-target disease. No new lesions. FA analysis set.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    172
    171
    Units: percentage of subjects
        number (confidence interval 95%)
    78.5 (71.6 to 84.4)
    68.4 (60.9 to 75.3)
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    The confidence interval for the difference in percentage was based on normal distribution
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    343
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0381
    Method
    Pearson chi-square test
    Parameter type
    Difference in percentage
    Point estimate
    10.067
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.8
         upper limit
    19.4

    Secondary: Time to progression (TTP) Based on IRR

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    End point title
    Time to progression (TTP) Based on IRR
    End point description
    TTP was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression according to RECIST v1.1 determined by IRR. Objective tumor progression was defined as 20% increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 mm or clear progression of pre-existing non-target lesions, or the appearance of any new clear lesions. If tumor progression data included more than 1 date, the first date was used. TTP (in months) was calculated as (first event date − randomization date +1)/30.44. FA population included all subjects who were randomized with study treatment assignment designated according to the initial randomization.
    End point type
    Secondary
    End point timeframe
    Randomization to objective progression or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    172
    171
    Units: months
        median (confidence interval 95%)
    13.6 (8.5 to 15)
    7 (6.8 to 8.3)
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    Analysis was based on the Cox Proportional hazards model assuming proportional hazards, a HR less than 1 indicated a reduction in hazard rate in favor of Crizotinib.
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    343
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001 [4]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.441
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.335
         upper limit
    0.582
    Notes
    [4] - P-value was obtained from 1-sided unstratified log-rank test.

    Secondary: Time to Intracranial Progression (IC-TTP) Based on IRR

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    End point title
    Time to Intracranial Progression (IC-TTP) Based on IRR
    End point description
    IC-TTP was defined similarly to TTP, but only considering intracranial disease (excluding extracranial disease) and the progression was determined based on either new brain metastases or progression of existing brain metastases. TTP was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression according to RECIST v1.1 determined by IRR. Objective tumor progression was defined as 20% increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 mm or clear progression of pre-existing non-target lesions, or the appearance of any new clear lesions. FA population included all subjects who were randomized with study treatment assignment designated according to the initial randomization.
    End point type
    Secondary
    End point timeframe
    Randomization to objective intracranial progression or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    172
    171
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    17.8 (13.9 to 99999)
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    Analysis was based on the Cox Proportional hazards model assuming proportional hazards, a HR less than 1 indicated a reduction in hazard rate in favor of Crizotinib.
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    343
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0347 [5]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.595
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.338
         upper limit
    1.048
    Notes
    [5] - P-value was obtained from 1-sided unstratified log-rank test.

    Secondary: Time to Extracranial Progression (EC-TTP) Based on IRR

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    End point title
    Time to Extracranial Progression (EC-TTP) Based on IRR
    End point description
    EC-TTP was defined similarly to TTP, but only considering extracranial disease (excluding intracranial disease) and the progression was determined based on either new extracranial lesions or progression of existing extracranial lesions. TTP was defined as the time from the date of randomization to the date of the first documentation of objective tumor progression according to RECIST v1.1 determined by IRR. Objective tumor progression was defined as 20% increase in the sum of the diameters of target measurable lesions taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study), with a minimum absolute increase of 5 mm or clear progression of pre-existing non-target lesions, or the appearance of any new clear lesions. FA population included all subjects who were randomized with study treatment assignment designated according to the initial randomization.
    End point type
    Secondary
    End point timeframe
    Randomization to objective extracranial progression or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    172
    171
    Units: months
        median (confidence interval 95%)
    15.2 (12.6 to 21.9)
    7.2 (6.9 to 8.5)
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    Analysis was based on the Cox Proportional hazards model assuming proportional hazards, a HR less than 1 indicated a reduction in hazard rate in favor of Crizotinib.
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    343
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001 [6]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.387
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.286
         upper limit
    0.524
    Notes
    [6] - P-value was obtained from 1-sided unstratified log-rank test.

    Secondary: Percentage of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Percentage of Subjects With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 28 days after last dose of study drug that were absent before treatment or that worsened relative to pretreatment state. AEs included both SAEs and non-SAEs. The safety analysis population included all randomized subjects who received at least 1 dose of study treatment, with treatment assignments designated according to actual study treatment received during the first cycle.
    End point type
    Secondary
    End point timeframe
    Baseline up to follow up period (up to 72 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    171
    169
    Units: percentage of subjects
    number (not applicable)
        AEs
    99.4
    99.4
        SAEs
    41.5
    29
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Treatment Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Percentage of Subjects With Treatment Emergent Treatment-Related Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    Treatment-related AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to 28 days after last dose of study drug that were absent before treatment or that worsened relative to pre-treatment state. Relatedness to study drug was assessed by the investigator. The safety analysis population included all randomized subjects who received at least 1 dose of study treatment, with treatment assignments designated according to actual study treatment received during the first cycle.
    End point type
    Secondary
    End point timeframe
    Baseline up to follow up period (up to 72 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    171
    169
    Units: percentage of subjects
    number (not applicable)
        AEs
    98.2
    92.3
        SAEs
    12.9
    8.9
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Adverse Events (AEs) According to Maximum Severity

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    End point title
    Percentage of Subjects With Adverse Events (AEs) According to Maximum Severity
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. AE was assessed according to maximum severity grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events [CTCAE] Version 3.0. Grade 1 =mild; Grade 2 =moderate; within normal limits, Grade 3 =severe or medically significant but not immediately life-threatening; Grade 4 =life-threatening or disabling; urgent intervention indicated; Grade 5 =death. The safety analysis population included all randomized subjects who received at least 1 dose of study treatment, with treatment assignments designated according to actual study treatment received during the first cycle.
    End point type
    Secondary
    End point timeframe
    Baseline up to follow up period (up to 72 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    171
    169
    Units: percentage of subjects
    number (not applicable)
        Grade 1
    7
    9.5
        Grade 2
    28.7
    34.3
        Grade 3
    41.5
    44.4
        Grade 4
    8.8
    8.9
        Grade 5
    13.5
    2.4
    No statistical analyses for this end point

    Secondary: Plasma Predose Concentration (Ctrough) of Crizotinib and its Metabolite PF-06260182

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    End point title
    Plasma Predose Concentration (Ctrough) of Crizotinib and its Metabolite PF-06260182 [7]
    End point description
    Ctrough is the concentration prior to study drug administration on Day 1 of Cycle 2 onwards. PF-06260182 is the metabolite of Crizotinib. The Pharmacokinetic concentration population included all subjects in the safety analysis population who had at least 1 plasma concentration of crizotinib or its metabolite.N= subjects who were evaluable for this measure. n= subjects who were evaluable at specified time points. This analysis was performed in crizotinib arm only.
    End point type
    Secondary
    End point timeframe
    Predose at Day 1 of Cycle 2, 3 and 5
    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: This endpoint was planned to be reported for Crizotinib arm only.
    End point values
    Crizotinib
    Number of subjects analysed
    162
    Units: nanogram per milliliter
    geometric mean (geometric coefficient of variation)
        Crizotinib Ctrough: Cycle 2 Day 1 (n= 91)
    324.2 ± 39
        Crizotinib Ctrough: Cycle 3 Day 1 (n= 85)
    320.9 ± 40
        Crizotinib Ctrough: Cycle 5 Day 1 (n= 82)
    308.2 ± 39
        PF-06260182 Ctrough: Cycle 2 Day 1 (n= 100)
    98.4 ± 46
        PF-06260182 Ctrough: Cycle 3 Day 1 (n= 94)
    99 ± 49
        PF-06260182 Ctrough: Cycle 5 Day 1 (n= 86)
    92.9 ± 55
    No statistical analyses for this end point

    Secondary: Percentage of Subjects For Each Anaplastic Lymphoma Kinase (ALK) Gene Fusion Variants

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    End point title
    Percentage of Subjects For Each Anaplastic Lymphoma Kinase (ALK) Gene Fusion Variants
    End point description
    The Response Genetics, Inc. Echinoderm Microtubule Associated Protein Like 4 (EML4) ALK reverse transcriptase polymerase chain reaction (RT PCR) gene fusion test was used for the analysis of tissue samples for the ALK gene fusion variants (either no rearrangement, or 1 of 9 results reflecting 8 specific rearrangements [V1, V2, V3a, V3b,V3a/b, V4, V5a, V6, V7]). Percentage of subjects who tested positive for ALK gene fusion variants were reported in this endpoint. The ALK variant evaluable population included subjects from the FA population who had a result from ALK gene fusion variant testing of either no rearrangement, or 1 of 9 results reflecting 8 specific rearrangements (V1, V2, V3a, V3b, V3a/b, V4, V5a, V6, and V7).
    End point type
    Secondary
    End point timeframe
    28 days prior to day 1 of study treatment
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    70
    78
    Units: percentage of subjects
    number (not applicable)
        V1
    27.1
    25.6
        V2
    7.1
    7.7
        V3a
    1.4
    1.3
        V3a/b
    4.3
    6.4
        No rearrangement
    60
    59
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) of Anaplastic Lymphoma Kinase (ALK) Variant Groups Based on IRR

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    End point title
    Objective Response Rate (ORR) of Anaplastic Lymphoma Kinase (ALK) Variant Groups Based on IRR
    End point description
    The Response Genetics, Inc. EML4 ALK RTPCR gene fusion test was used for the analysis of tissue samples for the ALK gene fusion variants (either no rearrangement, or 1 of 9 results reflecting 8 specific rearrangements [V1, V2, V3a, V3b,V3a/b, V4, V5a, V6, V7]). Percentage of subjects with confirmed CR or PR according to RECIST v1.1 determined by IRR, by type of ALK gene fusion variant were reported in this outcome measure. CR: complete disappearance of all target lesions and non-target disease. All nodes, both target and non-target, must decrease to normal (short axis<10 mm).No new lesions and disappearance of all non-target lesions.PR:>=30% decrease taking as reference the baseline sum of lesion dimensions. Short axis was used in sum for target nodes, while longest diameter was used in sum for all or target lesions. No clear progression of non-target disease. No new lesions. The ALK variant evaluable set. Here, n signifies those subjects who were evaluable at specified time points.
    End point type
    Secondary
    End point timeframe
    Randomization to objective progression, death or last tumor assessment without progression before any additional anti-cancer therapy (up to 35 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    70
    78
    Units: percentage of subjects
    number (confidence interval 95%)
        V1 (n =19,20)
    84.2 (60.4 to 96.6)
    45 (23.1 to 68.5)
        V2 (n =5,6)
    100 (47.8 to 100)
    33.3 (4.3 to 77.7)
        V3a (n =1,1)
    0 (-99999 to 99999)
    100 (2.5 to 100)
        V3a/b (n =3,5)
    100 (29.2 to 100)
    60 (14.7 to 94.7)
        No rearrangement (n =42,46)
    71.4 (55.4 to 84.3)
    43.5 (28.9 to 58.9)
    No statistical analyses for this end point

    Secondary: Time to Deterioration (TTD) in Chest Pain, Dyspnea or Cough

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    End point title
    Time to Deterioration (TTD) in Chest Pain, Dyspnea or Cough
    End point description
    TTD in pain in chest, dyspnea, or cough from the Quality of Life Questionnaire Core 30 (QLQ-LC13) was a composite endpoint defined as the time from randomization to the earliest time the subject scale scores showed a 10 point or greater increase after baseline in any of the 3 symptoms. For those who had not shown deterioration, the data was censored at the last date when the subjects completed an assessment (QLQ-LC13) for pain, dyspnea, or cough or at last visit date prior to crossover for subjects randomized to chemotherapy who crossed over to crizotinib. A 10-point or higher change in the score was perceived by subjects as clinically significant. The transformed score of pain, dyspnea, and cough symptom scales of EORTC (European Organization for the Research and Treatment of Cancer) QLQ-LC13 range from 0 to 100, where higher scores indicate greater symptom severity. The patient reported outcome (PRO) evaluable analysis set.
    End point type
    Secondary
    End point timeframe
    From randomization of treatment up to deterioration while on study treatment (up to 35 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    166
    163
    Units: months
        median (confidence interval 95%)
    2.1 (0.8 to 4.2)
    0.5 (0.4 to 0.7)
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    HR was calculated based on the Cox Proportional hazards model. Assuming proportional hazards, a HR less than 1 indicated a reduction in hazard rate in favor of crizotinib.
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0002 [8]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.591
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.452
         upper limit
    0.773
    Notes
    [8] - Two-sided p-value from the unstratified log rank test was used.

    Secondary: Change From Baseline in Functioning and Global Quality of Life (QOL) as Assessed by the 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
    Change From Baseline in Functioning and Global Quality of Life (QOL) as Assessed by the 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 5 functional scales (physical, role, cognitive, emotional and social), global health status/global quality of life scale, 3 symptom scales (fatigue, pain, nausea and vomiting), 6 single items that assess the additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, diarrhea) and financial difficulties. All scales and single-item measures range from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning, for the global health status/QoL represents a high QoL (better subject state), and for a symptom scale/item represents a high level of symptoms/problems (worse subject state). PRO evaluable population included all subjects from the FA population who completed a baseline and at least 1 postbaseline PRO assessment prior to end of randomized study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, From Cycle 1 Day 1 up to end of study treatment or crossover to crizotinib arm (up to 35 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    166
    163
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        QLQ-C30 Global QoL
    5.9815 (3.92 to 8.05)
    -7.8488 (-10.15 to -5.55)
        QLQ-C30 Cognitive Functioning
    1.1836 (-0.66 to 3.03)
    -2.1696 (-4.21 to -0.13)
        QLQ-C30 Emotional Functioning
    8.7431 (6.77 to 10.72)
    1.2266 (-0.95 to 3.4)
        QLQ-C30 Physical Functioning
    5.937 (3.94 to 7.93)
    -4.4664 (-6.59 to -2.34)
        QLQ-C30 Role Functioning
    4.8122 (1.92 to 7.71)
    -10.7391 (-13.87 to -7.61)
        QLQ-C30 Social Functioning
    4.379 (1.6 to 7.15)
    -4.3851 (-7.37 to -1.4)
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-C30 Global QoL: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    13.8303
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    10.74
         upper limit
    16.92
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-C30 cognitive functioning: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.017
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    3.3532
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    6.11
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-C30 emotional functioning: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    7.5165
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.57
         upper limit
    10.46
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-C30 physical functioning: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    10.4035
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    7.48
         upper limit
    13.32
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-C30 role functioning: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    15.5513
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.29
         upper limit
    19.81
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-C30 social functioning: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    8.7641
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.69
         upper limit
    12.84

    Secondary: Change From Baseline Scores in QLQ-C30 Symptoms as Assessed by the 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
    Change From Baseline Scores in QLQ-C30 Symptoms as Assessed by the 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 5 functional scales (physical, role, cognitive, emotional and social), global health status/global quality of life scale, 3 symptom scales (fatigue, pain, nausea and vomiting), 6 single items that assess the additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, diarrhea) and financial difficulties. All scales and single-item measures range from 0 to 100. A high score for a functional scale represents a high/healthy level of functioning, for the global health status/QoL represents a high QoL (better subject state), and for a symptom scale/item represents a high level of symptoms/problems (worse subject state). The PRO evaluable population included all subjects from the FA population who completed a baseline and at least 1 postbaseline PRO assessment prior to crossover to crizotinib or end of randomized study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, From Cycle 1 Day 1 up to end of study treatment or crossover to crizotinib arm (up to 35 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    166
    163
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        QLQ-C30 Appetite loss
    -5.4906 (-8.52 to -2.47)
    8.007 (4.63 to 11.38)
        QLQ-C30 Constipation
    6.4858 (3.46 to 9.51)
    10.9194 (7.5 to 14.34)
        QLQ-C30 Diarrhea
    12.9558 (10.67 to 15.24)
    0.4652 (-2.2 to 3.13)
        QLQ-C30 Dysponea
    -14.9019 (-17.4 to -12.4)
    -1.4398 (-4.21 to 1.33)
        QLQ-C30 Fatigue
    -7.3476 (-9.72 to -4.98)
    7.6511 (5.05 to 10.25)
        QLQ-C30 Financial Difficulties
    -0.5984 (-3.13 to 1.93)
    0.2203 (-2.54 to 2.98)
        QLQ-C30 Insomnia
    -10.3095 (-13.1 to -7.52)
    -0.2665 (-3.38 to 2.84)
        QLQ-C30 Nausea and Vomiting
    3.7742 (1.54 to 6.01)
    7.2188 (4.66 to 9.78)
        QLQ-C30 Pain
    -11.0993 (-13.27 to -8.92)
    -1.1716 (-3.66 to 1.31)
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-C30 appetite loss: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -13.4976
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.03
         upper limit
    -8.97
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-C30 constipation: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.057
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -4.4336
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9
         upper limit
    0.13
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-C30 diarrhea: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    12.4906
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.98
         upper limit
    16
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-C30 dysponea: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -13.4622
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.2
         upper limit
    -9.73
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-C30 fatigue: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -14.9987
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.52
         upper limit
    -11.48
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-C30 financial difficulties: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.6681
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.8186
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.56
         upper limit
    2.92
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-C30 insomnia: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -10.043
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.22
         upper limit
    -5.87
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-C30 nausea and vomiting: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0468
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -3.4446
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.84
         upper limit
    -0.05
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-C30 pain: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-C30 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -9.9277
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.23
         upper limit
    -6.62

    Secondary: Change From Baseline in Lung Cancer Symptom Scores as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13)

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    End point title
    Change From Baseline in Lung Cancer Symptom Scores as Assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Lung Cancer 13 (QLQ- LC13)
    End point description
    QLQ-LC13 consists of 1 multi-item scale and 9 single items that assess the specific symptoms (dyspnea, cough, hemoptysis, and site-specific pain), side effects (sore mouth, dysphagia, neuropathy, and alopecia), and pain medication use of patients with lung cancer receiving chemotherapy. All multi-item scales and single-item measures range from 0 to 100, where higher score indicates greater degree of symptom severity. The PRO evaluable population included all subjects from the FA population who completed a baseline and at least 1 postbaseline PRO assessment prior to crossover to crizotinib or end of randomized study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline, From Cycle 1 day 1 up to end of study treatment or crossover to crizotinib arm (up to 35 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    166
    163
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        QLQ-LC13 Alopecia
    -4.4879 (-6.99 to -1.99)
    0.3271 (-2.4 to 3.06)
        QLQ-LC13 Coughing
    -16.4819 (-18.92 to -14.05)
    -8.0893 (-10.83 to -5.35)
        QLQ-LC13 Dysphagia
    0.7618 (-0.82 to 2.35)
    0.0966 (-1.76 to 1.95)
        QLQ-LC13 Dyspnoea
    -9.2029 (-11.2 to -7.2)
    -0.1948 (-2.36 to 1.97)
        QLQ-LC13 Haemoptysis
    -3.2197 (-3.83 to -2.61)
    -2.3369 (-3.05 to -1.62)
        QLQ-LC13 Pain in Arm or Shoulder
    -10.1693 (-12.26 to -8.08)
    -4.1218 (-6.51 to -1.74)
        QLQ-LC13 Pain in Chest
    -8.1437 (-10.31 to -5.98)
    -0.0479 (-2.48 to 2.38)
        QLQ-LC13 Pain in Other Parts
    -8.0757 (-10.28 to -5.87)
    -1.304 (-3.97 to 1.36)
        QLQ-LC13 Peripheral Neuropathy
    3.1779 (1.04 to 5.31)
    -0.1742 (-2.6 to 2.25)
        QLQ-LC13 Sore Mouth
    2.2472 (0.36 to 4.13)
    4.3993 (2.27 to 6.53)
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-LC13 alopecia: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0108
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -4.8149
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.52
         upper limit
    -1.11
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-LC13 coughing: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -8.3926
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -12.06
         upper limit
    -4.72
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-LC13 dysphagia: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.5938
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    0.6651
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.78
         upper limit
    3.11
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-LC13 dyspnoea: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -9.008
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.96
         upper limit
    -6.06
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-LC13 haemoptysis: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0656
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -0.8828
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.82
         upper limit
    0.06
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-LC13 pain in arm or shoulder: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0002
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -6.0475
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.22
         upper limit
    -2.88
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-LC13 pain in chest: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -8.0959
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.35
         upper limit
    -4.84
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-LC13 pain in other parts: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -6.7717
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.24
         upper limit
    -3.31
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-LC13 peripheral neuropathy: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0427
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    3.3521
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.11
         upper limit
    6.59
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    QLQ-LC13 sore mouth: Analysis was from a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EORTC QLQ-LC13 subscale baseline score (intercept and time from first dose are included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.1382
    Method
    Mixed models analysis
    Parameter type
    Mean difference (net)
    Point estimate
    -2.1521
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5
         upper limit
    0.69

    Secondary: Change From Baseline in General Health Status as Assessed by EuroQol 5D (EQ-5D)- Visual Analog Scale (VAS)

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    End point title
    Change From Baseline in General Health Status as Assessed by EuroQol 5D (EQ-5D)- Visual Analog Scale (VAS)
    End point description
    EQ-5D: subject rated questionnaire to assess health-related quality of life in terms of a single index value. VAS component: subjects rated their current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health. The PRO evaluable population included all subjects from the FA population who completed a baseline and at least 1 postbaseline PRO assessment prior to crossover to crizotinib or end of randomized study treatment. Here, "N" signifies participants who were evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, From Cycle 1 day 1 up to end of study treatment or crossover to crizotinib arm (up to 35 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    160
    160
    Units: units on a scale
        arithmetic mean (confidence interval 95%)
    4.5323 (2.44 to 6.62)
    0.5415 (-1.85 to 2.93)
    Statistical analysis title
    Crizotinib vs Chemotherapy
    Statistical analysis description
    Analysis was based on a repeated measures mixed-effects model with an intercept term, treatment, treatment-by-time interaction, and baseline EQ-5D VAS subscale baseline score (intercept and time from first dose were included as random effects).
    Comparison groups
    Crizotinib v Chemotherapy
    Number of subjects included in analysis
    320
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0139
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    3.9908
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.81
         upper limit
    7.17

    Secondary: Percentage of Subjects with Hospital Admissions-Healthcare Resource Utilization (HCRU)

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    End point title
    Percentage of Subjects with Hospital Admissions-Healthcare Resource Utilization (HCRU)
    End point description
    Healthcare resource utilization was to be evaluated using the assessment of the following: date and duration of index admission, duration of hospitalization and date of discharge. FA population included all subjects who were randomized with study treatment assignment designated according to the initial randomization.
    End point type
    Secondary
    End point timeframe
    Baseline up to follow up period (up to 72 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    172
    171
    Units: percentage of subjects
        number (not applicable)
    40.12
    36.26
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Hematological Test Abnormalities

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    End point title
    Percentage of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Hematological Test Abnormalities
    End point description
    Anemia (grade[g]1:Less than[<]Lower limit of normal[LLN] to 10gram per[/]deciliter[g/dL],g2:<10 to 8g/dL,g3:<8g/dL,g4:lifethreatening); platelet (g1:<LLN to 75*10^3/mm]^3,g2:<75*10^3/mm^3 to 50*10^3/mm^3,g3:<50*10^3/mm^3 to 25*10^3/mm^3,g4:<25*10^3/mm^3);lymphopenia(g1:<LLN to 8*10^2/mm^3,g2:<8*10^2 to 5*10^2/mm^3,g3:<5*10^2 to 2*10^2/mm^3,g4:<2*10^2/mm^3); neutrophil(g1:<LLN to 15*10^2/mm^3,g2:<15*10^2 to 10*10^2/mm^3,g3:<10*10^2 to 5*10^2/mm^3,g4:<5*10^2/mm^3);WBC(g1:<LLN to 3*10^3/mm^3,g2:<3*10^3 to 2*10^3/mm^3,g3:<2*10^3 to 1*10^3/mm^3,g4:<1*10^3/mm^3); haemoglobin (Hgb) (g1:increase in Hgb level>0 to 2 g/dL above ULN or above baseline if baseline is above ULN,g2:increase in Hgb level>2 to 4g/dL above ULN or above baseline if baseline is above ULN,g3:increase in Hgb level>4 g/dL above ULN or above baseline if baseline is above ULN). Subject>=1 abnormality given. Safety analysis set. N=subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to follow up period (up to 72 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    170
    165
    Units: percentage of subjects
    number (not applicable)
        Anemia: Grade 1
    47.1
    46.7
        Anemia: Grade 2
    13.5
    27.9
        Anemia: Grade 3
    0.6
    10.9
        Hemoglobin increased: Grade 1
    6.5
    3
        Hemoglobin increased: Grade 2
    0.6
    0
        Lymphocyte count increased: Grade 2
    3.5
    1.2
        Lymphopenia: Grade 1
    34.1
    26.1
        Lymphopenia: Grade 2
    24.7
    33.9
        Lymphopenia: Grade 3
    10.6
    13.9
        Lymphopenia: Grade 4
    2.4
    1.8
        Neutrophils (Absolute): Grade 1
    20.6
    14.5
        Neutrophils (Absolute): Grade 2
    20
    26.7
        Neutrophils (Absolute): Grade 3
    14.1
    13.9
        Neutrophils (Absolute): Grade 4
    0.6
    3.6
        Platelets: Grade 1
    9.4
    21.8
        Platelets: Grade 2
    2.4
    7.9
        Platelets: Grade 3
    0.6
    7.9
        Platelets: Grade 4
    0
    0.6
        White blood cells: Grade 1
    23.5
    34.5
        White blood cells: Grade 2
    22.5
    24.2
        White blood cells: Grade 3
    2.9
    9.1
        White blood cells: Grade 4
    0
    0.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Chemistry Test Abnormalities

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    End point title
    Percentage of Subjects With Laboratory Test Abnormalities By Maximum Severity: National Cancer Institute Common Terminology Criteria for Adverse Event (Version 4.0) Grade 1 to 4 Chemistry Test Abnormalities
    End point description
    ALT/AST([g]1:>ULN-3*ULN,g2:>3-5*ULN,g3:>5-20*ULN,g4:>20*ULN);AP(g1:>ULN-2.5*ULN,g2:>2.5-5*ULN,g3:>5-20*ULN,g4:>20*ULN);CR(g1:>ULN-1.5*ULN,g2:>1.5-3*ULN,g3:>3-6*ULN,g4:>6*ULN);hyperglycemia(g1:>ULN-160,g2:>160-250,g3:>250-500,g4:>500mg/dL);bilirubin(total) (g1:>ULN-1.5*ULN,g2:>1.5-3*ULN,g3:>3-10*ULN,g4:>10*ULN);hypoglycaemia (g1:<LLN-55,g2:<55-40,g3:<40-30,g4:<30mg/dL);hyperkalemia (g1:>ULN-5.5,g2:>5.5-6,g3:>6-7,g4:>7mmol/L);hypokalemia (g1:<LLN-3,g2:<LLN-3,g3:<3-2.5,g4:<2.5mmol/L);hypermagnesemia (g1:>ULN-3,g3:>3-8,g4:>8mg/dL);hypocalcemia (g1:<LLN-8,g2:<8-7,g3:<7-6,g4:<6mg/dL);hypercalcemia (g1:>ULN-11.5,g2:>11.5-12.5,g3:>12.5-13.5,g4:>13.5mg/dL);hypomagnesemia (g1:<LLN-1.2,g2:<1.2-0.9,g3:<0.9-0.7,g4:<0.7mg/dL);hyponatremia (g1:<LLN-130,g3:<130-120,g4:<120mmol/L);hypoalbuminemia (g1:<LLN-3,g2:<3-2,g3:<2,g4:lifethreatening);hypophosphatemia (g1:<LLN-2.5,g2:<2.5-2,g3:<2-1,g4:<1mg/dL).Safety set.N= subjects evaluable for this endpoint,n=subjects evaluable at specific time points.
    End point type
    Secondary
    End point timeframe
    Baseline up to follow up period (up to 72 months)
    End point values
    Crizotinib Chemotherapy
    Number of subjects analysed
    171
    165
    Units: percentage of subjects
    number (not applicable)
        Alanine aminotransferase: Grade 1 (n =171, 165)
    64.3
    34.5
        Alanine aminotransferase: Grade 2 (n =171, 165)
    10.5
    7.3
        Alanine aminotransferase: Grade 3 (n =171, 165)
    12.3
    1.8
        Alanine aminotransferase: Grade 4 (n =171, 165)
    2.3
    0
        Alkaline phosphatase: Grade 1 (n =171, 165)
    55.6
    33.9
        Alkaline phosphatase: Grade 2 (n =171, 165)
    8.8
    4.8
        Alkaline phosphatase: Grade 3 (n =171, 165)
    0.6
    1.2
        Aspartate Aminotransferase: Grade 1 (n =171, 165)
    57.9
    32.1
        Aspartate Aminotransferase: Grade 2 (n =171, 165)
    6.4
    1.8
        Aspartate Aminotransferase: Grade 3 (n =171, 165)
    7.6
    1.2
        Aspartate Aminotransferase: Grade 4 (n =171, 165)
    0.6
    0
        Bilirubin: Grade 1 (n =171, 165)
    10.5
    7.3
        Bilirubin: Grade 2 (n =171, 165)
    5.8
    1.2
        Bilirubin: Grade 3 (n =171, 165)
    0
    0.6
        Creatinine: Grade 1 (n =171, 165)
    50.3
    78.8
        Creatinine: Grade 2 (n =171, 165)
    47.4
    15.8
        Creatinine: Grade 3 (n =171, 165)
    1.2
    0
        Hypercalcemia: Grade 1 (n =171, 165)
    0.6
    9.1
        Hypercalcemia: Grade 4 (n =171, 165)
    0.6
    0
        Hyperglycemia: Grade 1 (n =171, 165)
    50.3
    42.4
        Hyperglycemia: Grade 2 (n =171, 165)
    15.8
    23.6
        Hyperglycemia: Grade 3 (n =171, 165)
    4.1
    3.6
        Hyperkalemia: Grade 1 (n =171, 165)
    17.5
    12.1
        Hyperkalemia: Grade 2 (n =171, 165)
    5.8
    3
        Hyperkalemia: Grade 3 (n =171, 165)
    2.3
    1.8
        Hyperkalemia: Grade 4 (n =171, 165)
    0.6
    0
        Hypermagnesemia: Grade 1 (n =170, 162)
    17.6
    8
        Hypermagnesemia: Grade 3 (n =170, 162)
    1.8
    0
        Hypernatremia: Grade 1 (n =171, 165)
    21.1
    5.5
        Hypernatremia: Grade 2 (n =171, 165)
    0.6
    0
        Hypernatremia: Grade 4 (n =171, 165)
    0.6
    0
        Hypoalbuminemia: Grade 1 (n =171, 164)
    35.1
    22.6
        Hypoalbuminemia: Grade 2 (n =171, 164)
    44.4
    14.6
        Hypoalbuminemia: Grade 3 (n =171, 164)
    1.2
    0.6
        Hypocalcemia: Grade 1 (n =171, 165)
    39.8
    24.8
        Hypocalcemia: Grade 2 (n =171, 165)
    38
    4.8
        Hypocalcemia: Grade 3 (n =171, 165)
    2.3
    0.6
        Hypoglycemia: Grade 1 (n =171, 165)
    19.9
    3.6
        Hypoglycemia: Grade 2 (n =171, 165)
    4.7
    1.8
        Hypoglycemia: Grade 4 (n =171, 165)
    0
    0.6
        Hypokalemia: Grade 1 (n =171, 165)
    14.6
    9.1
        Hypokalemia: Grade 3 (n =171, 165)
    2.3
    3
        Hypokalemia: Grade 4 (n =171, 165)
    0
    0.6
        Hypomagnesemia: Grade 1 (n =170, 162)
    12.4
    26.5
        Hypomagnesemia: Grade 2 (n =170, 162)
    0
    1.9
        Hyponatremia: Grade 1 (n =171, 165)
    25.7
    22.4
        Hyponatremia: Grade 3 (n =171, 165)
    4.1
    5.5
        Hyponatremia: Grade 4 (n =171, 165)
    0.6
    1.2
        Hypophosphatemia: Grade 1 (n =169, 161)
    5.3
    3.1
        Hypophosphatemia: Grade 2 (n =169, 161)
    27.2
    13
        Hypophosphatemia: Grade 3 (n =169, 161)
    13
    6.8
        Hypophosphatemia: Grade 4 (n =169, 161)
    1.2
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to follow up period (up to 72 months)
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Chemotherapy
    Reporting group description
    Standard doses of chemotherapy (pemetrexed/cisplatin or pemetrexed/carboplatin) were administered intravenously, where pemetrexed 500 mg/m^2 IV infusion according to standard of care was administered over 10 min; cisplatin 75mg/m^2 IV infusion was administered approximately 30 min after the end of the pemetrexed infusion and carboplatin was administered at a dose calculated to produce an AUC of 5 or 6 mg*min/mL, approximately 30 minutes after end of pemetrexed infusion.

    Reporting group title
    Crizotinib
    Reporting group description
    Crizotinib 250 mg capsule, orally twice daily was administered in treatment cycle of 21 days (up to a maximum of 50 cycles). Subjects could continue crizotinib treatment beyond the time of RECIST v1.1 defined PD, as determined by IRR, at the discretion of the investigator if the subject was perceived to be experiencing clinical benefit.

    Serious adverse events
    Chemotherapy Crizotinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 169 (28.99%)
    71 / 171 (41.52%)
         number of deaths (all causes)
    81
    71
         number of deaths resulting from adverse events
    4
    23
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic dissection
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (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)
    Thyroid adenoma
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Unintended pregnancy
    Additional description: This adverse event is gender specific.
         subjects affected / exposed [1]
    0 / 108 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    1 / 169 (0.59%)
    18 / 171 (10.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 19
         deaths causally related to treatment / all
    1 / 1
    18 / 18
    Fatigue
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 169 (1.18%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hypomania
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed [2]
    0 / 108 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (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
    0 / 169 (0.00%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Asthma
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    4 / 169 (2.37%)
    7 / 171 (4.09%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    5 / 169 (2.96%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    7 / 169 (4.14%)
    5 / 171 (2.92%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    acute respiratory distress syndrome
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenopathy mediastinal
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system lesion
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (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
    0 / 169 (0.00%)
    3 / 171 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicobrachial syndrome
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (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 / 169 (0.00%)
    1 / 171 (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 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    5 / 169 (2.96%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 169 (0.59%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 169 (0.59%)
    4 / 171 (2.34%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 169 (0.00%)
    3 / 171 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 169 (2.37%)
    3 / 171 (1.75%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (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
    Haematuria
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst
         subjects affected / exposed
    0 / 169 (0.00%)
    3 / 171 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (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 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (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
    0 / 169 (0.00%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 169 (1.18%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hypokalaemia
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 169 (0.59%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoproteinaemia
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (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
    Abdominal abscess
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (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
    0 / 169 (0.00%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 169 (0.59%)
    3 / 171 (1.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 169 (0.59%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 169 (0.59%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 169 (0.00%)
    2 / 171 (1.17%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 169 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: As this adverse event is gender specific, so the number of subjects at risk is equal to the number of female subjects in the study.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: As this adverse event is gender specific, so the number of subjects at risk is equal to the number of female subjects in the study.
    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
    165 / 169 (97.63%)
    168 / 171 (98.25%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    40 / 169 (23.67%)
    28 / 171 (16.37%)
         occurrences all number
    71
    47
    Chest pain
         subjects affected / exposed
    14 / 169 (8.28%)
    21 / 171 (12.28%)
         occurrences all number
    18
    26
    Fatigue
         subjects affected / exposed
    66 / 169 (39.05%)
    54 / 171 (31.58%)
         occurrences all number
    105
    99
    Mucosal inflammation
         subjects affected / exposed
    9 / 169 (5.33%)
    2 / 171 (1.17%)
         occurrences all number
    11
    2
    Oedema peripheral
         subjects affected / exposed
    12 / 169 (7.10%)
    89 / 171 (52.05%)
         occurrences all number
    18
    189
    Pyrexia
         subjects affected / exposed
    17 / 169 (10.06%)
    40 / 171 (23.39%)
         occurrences all number
    24
    61
    Influenza like illness
         subjects affected / exposed
    1 / 169 (0.59%)
    10 / 171 (5.85%)
         occurrences all number
    1
    14
    Pain
         subjects affected / exposed
    5 / 169 (2.96%)
    9 / 171 (5.26%)
         occurrences all number
    9
    13
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    9 / 169 (5.33%)
    10 / 171 (5.85%)
         occurrences all number
    10
    14
    Insomnia
         subjects affected / exposed
    15 / 169 (8.88%)
    23 / 171 (13.45%)
         occurrences all number
    21
    26
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    21 / 169 (12.43%)
    59 / 171 (34.50%)
         occurrences all number
    48
    184
    Aspartate aminotransferase increased
         subjects affected / exposed
    16 / 169 (9.47%)
    47 / 171 (27.49%)
         occurrences all number
    30
    120
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 169 (1.18%)
    11 / 171 (6.43%)
         occurrences all number
    2
    21
    Neutrophil count decreased
         subjects affected / exposed
    17 / 169 (10.06%)
    14 / 171 (8.19%)
         occurrences all number
    44
    58
    Platelet count decreased
         subjects affected / exposed
    19 / 169 (11.24%)
    1 / 171 (0.58%)
         occurrences all number
    33
    1
    Weight decreased
         subjects affected / exposed
    5 / 169 (2.96%)
    12 / 171 (7.02%)
         occurrences all number
    7
    31
    Weight increased
         subjects affected / exposed
    4 / 169 (2.37%)
    16 / 171 (9.36%)
         occurrences all number
    9
    34
    White blood cell count decreased
         subjects affected / exposed
    12 / 169 (7.10%)
    11 / 171 (6.43%)
         occurrences all number
    25
    84
    Blood bilirubin increased
         subjects affected / exposed
    2 / 169 (1.18%)
    9 / 171 (5.26%)
         occurrences all number
    4
    21
    Blood creatinine increased
         subjects affected / exposed
    5 / 169 (2.96%)
    9 / 171 (5.26%)
         occurrences all number
    5
    9
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 169 (0.00%)
    22 / 171 (12.87%)
         occurrences all number
    0
    33
    Sinus bradycardia
         subjects affected / exposed
    1 / 169 (0.59%)
    10 / 171 (5.85%)
         occurrences all number
    1
    11
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    53 / 169 (31.36%)
    18 / 171 (10.53%)
         occurrences all number
    101
    27
    Leukopenia
         subjects affected / exposed
    16 / 169 (9.47%)
    8 / 171 (4.68%)
         occurrences all number
    47
    21
    Thrombocytopenia
         subjects affected / exposed
    14 / 169 (8.28%)
    1 / 171 (0.58%)
         occurrences all number
    36
    1
    Neutropenia
         subjects affected / exposed
    36 / 169 (21.30%)
    32 / 171 (18.71%)
         occurrences all number
    107
    203
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    28 / 169 (16.57%)
    44 / 171 (25.73%)
         occurrences all number
    35
    75
    Dyspnoea
         subjects affected / exposed
    23 / 169 (13.61%)
    31 / 171 (18.13%)
         occurrences all number
    32
    45
    Haemoptysis
         subjects affected / exposed
    6 / 169 (3.55%)
    11 / 171 (6.43%)
         occurrences all number
    7
    13
    Oropharyngeal pain
         subjects affected / exposed
    8 / 169 (4.73%)
    14 / 171 (8.19%)
         occurrences all number
    8
    18
    Productive cough
         subjects affected / exposed
    8 / 169 (4.73%)
    15 / 171 (8.77%)
         occurrences all number
    9
    18
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    15 / 169 (8.88%)
    35 / 171 (20.47%)
         occurrences all number
    25
    54
    Dysgeusia
         subjects affected / exposed
    9 / 169 (5.33%)
    45 / 171 (26.32%)
         occurrences all number
    9
    64
    Headache
         subjects affected / exposed
    25 / 169 (14.79%)
    48 / 171 (28.07%)
         occurrences all number
    30
    74
    Neuropathy peripheral
         subjects affected / exposed
    12 / 169 (7.10%)
    4 / 171 (2.34%)
         occurrences all number
    12
    4
    Paraesthesia
         subjects affected / exposed
    8 / 169 (4.73%)
    29 / 171 (16.96%)
         occurrences all number
    11
    36
    Peripheral sensory neuropathy
         subjects affected / exposed
    10 / 169 (5.92%)
    6 / 171 (3.51%)
         occurrences all number
    14
    7
    Eye disorders
    Photopsia
         subjects affected / exposed
    2 / 169 (1.18%)
    18 / 171 (10.53%)
         occurrences all number
    2
    30
    Vision blurred
         subjects affected / exposed
    5 / 169 (2.96%)
    13 / 171 (7.60%)
         occurrences all number
    5
    16
    Visual impairment
         subjects affected / exposed
    5 / 169 (2.96%)
    98 / 171 (57.31%)
         occurrences all number
    5
    123
    Vitreous floaters
         subjects affected / exposed
    1 / 169 (0.59%)
    11 / 171 (6.43%)
         occurrences all number
    1
    12
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    10 / 169 (5.92%)
    4 / 171 (2.34%)
         occurrences all number
    10
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    8 / 169 (4.73%)
    25 / 171 (14.62%)
         occurrences all number
    8
    37
    Abdominal pain upper
         subjects affected / exposed
    10 / 169 (5.92%)
    27 / 171 (15.79%)
         occurrences all number
    17
    34
    Constipation
         subjects affected / exposed
    51 / 169 (30.18%)
    78 / 171 (45.61%)
         occurrences all number
    68
    135
    Diarrhoea
         subjects affected / exposed
    22 / 169 (13.02%)
    111 / 171 (64.91%)
         occurrences all number
    25
    269
    Dyspepsia
         subjects affected / exposed
    5 / 169 (2.96%)
    27 / 171 (15.79%)
         occurrences all number
    7
    41
    Dysphagia
         subjects affected / exposed
    3 / 169 (1.78%)
    19 / 171 (11.11%)
         occurrences all number
    4
    25
    Gastrooesophageal reflux disease
         subjects affected / exposed
    6 / 169 (3.55%)
    14 / 171 (8.19%)
         occurrences all number
    7
    18
    Nausea
         subjects affected / exposed
    98 / 169 (57.99%)
    100 / 171 (58.48%)
         occurrences all number
    206
    246
    Stomatitis
         subjects affected / exposed
    17 / 169 (10.06%)
    13 / 171 (7.60%)
         occurrences all number
    28
    23
    Vomiting
         subjects affected / exposed
    57 / 169 (33.73%)
    87 / 171 (50.88%)
         occurrences all number
    89
    223
    Abdominal distension
         subjects affected / exposed
    1 / 169 (0.59%)
    11 / 171 (6.43%)
         occurrences all number
    1
    11
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    17 / 169 (10.06%)
    16 / 171 (9.36%)
         occurrences all number
    18
    17
    Pruritus
         subjects affected / exposed
    10 / 169 (5.92%)
    9 / 171 (5.26%)
         occurrences all number
    11
    13
    Rash
         subjects affected / exposed
    20 / 169 (11.83%)
    22 / 171 (12.87%)
         occurrences all number
    23
    27
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 169 (6.51%)
    25 / 171 (14.62%)
         occurrences all number
    12
    42
    Back pain
         subjects affected / exposed
    20 / 169 (11.83%)
    35 / 171 (20.47%)
         occurrences all number
    25
    58
    Bone pain
         subjects affected / exposed
    4 / 169 (2.37%)
    12 / 171 (7.02%)
         occurrences all number
    4
    24
    Muscle spasms
         subjects affected / exposed
    2 / 169 (1.18%)
    17 / 171 (9.94%)
         occurrences all number
    2
    21
    Musculoskeletal pain
         subjects affected / exposed
    8 / 169 (4.73%)
    21 / 171 (12.28%)
         occurrences all number
    12
    26
    Pain in extremity
         subjects affected / exposed
    14 / 169 (8.28%)
    44 / 171 (25.73%)
         occurrences all number
    17
    61
    Flank pain
         subjects affected / exposed
    2 / 169 (1.18%)
    9 / 171 (5.26%)
         occurrences all number
    2
    11
    Muscular weakness
         subjects affected / exposed
    4 / 169 (2.37%)
    9 / 171 (5.26%)
         occurrences all number
    4
    14
    Musculoskeletal chest pain
         subjects affected / exposed
    5 / 169 (2.96%)
    10 / 171 (5.85%)
         occurrences all number
    7
    12
    Myalgia
         subjects affected / exposed
    6 / 169 (3.55%)
    14 / 171 (8.19%)
         occurrences all number
    8
    16
    Neck pain
         subjects affected / exposed
    2 / 169 (1.18%)
    11 / 171 (6.43%)
         occurrences all number
    2
    12
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    58 / 169 (34.32%)
    59 / 171 (34.50%)
         occurrences all number
    108
    99
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 169 (1.18%)
    19 / 171 (11.11%)
         occurrences all number
    5
    31
    Hypomagnesaemia
         subjects affected / exposed
    13 / 169 (7.69%)
    3 / 171 (1.75%)
         occurrences all number
    17
    3
    Hypocalcaemia
         subjects affected / exposed
    1 / 169 (0.59%)
    10 / 171 (5.85%)
         occurrences all number
    1
    14
    Hypophosphataemia
         subjects affected / exposed
    2 / 169 (1.18%)
    10 / 171 (5.85%)
         occurrences all number
    2
    13
    Hypoproteinaemia
         subjects affected / exposed
    0 / 169 (0.00%)
    10 / 171 (5.85%)
         occurrences all number
    0
    28
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 169 (2.96%)
    30 / 171 (17.54%)
         occurrences all number
    6
    63
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 169 (7.69%)
    41 / 171 (23.98%)
         occurrences all number
    15
    99
    Bronchitis
         subjects affected / exposed
    2 / 169 (1.18%)
    11 / 171 (6.43%)
         occurrences all number
    4
    15
    Conjunctivitis
         subjects affected / exposed
    10 / 169 (5.92%)
    3 / 171 (1.75%)
         occurrences all number
    11
    4
    Rhinitis
         subjects affected / exposed
    2 / 169 (1.18%)
    9 / 171 (5.26%)
         occurrences all number
    2
    11
    Urinary tract infection
         subjects affected / exposed
    2 / 169 (1.18%)
    10 / 171 (5.85%)
         occurrences all number
    2
    13

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jul 2015
    Extended survival followup period to 36 months after the randomization of the last subject, to enhance the likelihood to obtain an estimate of the median overall survival.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    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
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