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    Clinical Trial Results:
    An Open-Label, Multicenter, Randomized, Phase 2 Study Evaluating the Safety and Efficacy of Cisplatin and Pemetrexed with or without Cixutumumab as First-Line Therapy in Patients with Advanced Nonsquamous Non-Small Cell Lung Carcinoma

    Summary
    EudraCT number
    		 2010-024014-60
    Trial protocol
    		 DE   IT   BE  
    Global end of trial date
    10 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jun 2017
    First version publication date
    25 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    I5A-MC-JAEM
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01232452
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial ID: 13973
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon - Fri, 9 AM - 5 PM EST, Eli Lilly and Company, 1 877-285-4559,
    Scientific contact
    Available Mon - Fri, 9 AM - 5 PM EST, Eli Lilly and Company, 1 877-CTLilly,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the hypothesis that cixutumumab given in combination with cisplatin and pemetrexed is superior to cisplatin and pemetrexed as first-line therapy for patients with advanced nonsquamous non-small cell lung carcinoma (NSCLC) as measured by progression-free survival (PFS).
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Apr 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 1 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 25
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Argentina: 13
    Country: Number of subjects enrolled
    Brazil: 36
    Country: Number of subjects enrolled
    Turkey: 12
    Country: Number of subjects enrolled
    United States: 21
    Country: Number of subjects enrolled
    Israel: 8
    Country: Number of subjects enrolled
    Spain: 13
    Worldwide total number of subjects
    172
    EEA total number of subjects
    80
    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)
    126
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 No Text Entered

    Pre-assignment
    Screening details
    		 Completers are those participants who died or had progressive disease (PD).

    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
    		 Pemetrexed + Cisplatin + Cixutumumab
    Arm description
    		 Induction Treatment: Pemetrexed 500 mg/m^2 plus cisplatin 75 mg/m^2 plus cixutumumab 20 mg/kg given intravenously (IV) on Day 1 of a 21 day cycle for up to 4 cycles. Two additional cycles of cisplatin may be given (6 cycles total) for participants with significant tumor size reduction, after sponsor approval. Maintenance Therapy: Pemetrexed 500 mg/m^2 plus cixutumumab 20 mg/kg given IV every 21 days until progression of disease, unacceptable toxicity, or another withdrawal criterion is met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pemetrexed 500 mg/m^2 was given IV on Day 1 of a 21 day cycle for up to 4 cycles.

    Investigational medicinal product name
    cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    cisplatin 75 mg/m^2 was given IV on Day 1 of a 21 day cycle for up to 4 cycles. Two additional cycles of cisplatin may be given (6 cycles total) for participants with significant tumor size reduction, after sponsor approval.

    Investigational medicinal product name
    cixutumumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    20 mg/kg given IV on Day 1 of a 21 day cycle for up to 4 cycles.

    Arm title
    		 Pemetrexed + Cisplatin
    Arm description
    		 Induction Treatment: Pemetrexed 500 mg/m^2 plus cisplatin 75 mg/m^2 given IV on Day 1 of a 21 day cycle for up to 4 cycles. Two additional cycles of cisplatin may be given (6 cycles total) for participants with significant tumor size reduction, after sponsor approval. Maintenance Therapy: Pemetrexed 500 mg/m^2 given IV every 21 days until progression of disease, unacceptable toxicity, or another withdrawal criterion is met.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pemetrexed 500 mg/m^2 was given IV on Day 1 of a 21 day cycle for up to 4 cycles.

    Investigational medicinal product name
    cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 75 mg/m^2 was given IV on Day 1 of a 21 day cycle for up to 4 cycles. Two additional cycles of cisplatin may be given (6 cycles total) for participants with significant tumor size reduction, after sponsor approval.

    Number of subjects in period 1
    		Pemetrexed + Cisplatin + Cixutumumab Pemetrexed + Cisplatin
    Started
    87
    85
    Received at least one dose of study drug
    85
    81
    Completed
    48
    46
    Not completed
    39
    39
         Consent withdrawn by subject
    11
    8
         Physician decision
    8
    12
         Adverse event, non-fatal
    17
    15
         Sponsor Decision
    3
    1
         Protocol entry criterion not met
    -
    1
         Protocol deviation
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pemetrexed + Cisplatin + Cixutumumab
    Reporting group description
    		 Induction Treatment: Pemetrexed 500 mg/m^2 plus cisplatin 75 mg/m^2 plus cixutumumab 20 mg/kg given intravenously (IV) on Day 1 of a 21 day cycle for up to 4 cycles. Two additional cycles of cisplatin may be given (6 cycles total) for participants with significant tumor size reduction, after sponsor approval. Maintenance Therapy: Pemetrexed 500 mg/m^2 plus cixutumumab 20 mg/kg given IV every 21 days until progression of disease, unacceptable toxicity, or another withdrawal criterion is met.

    Reporting group title
    Pemetrexed + Cisplatin
    Reporting group description
    		 Induction Treatment: Pemetrexed 500 mg/m^2 plus cisplatin 75 mg/m^2 given IV on Day 1 of a 21 day cycle for up to 4 cycles. Two additional cycles of cisplatin may be given (6 cycles total) for participants with significant tumor size reduction, after sponsor approval. Maintenance Therapy: Pemetrexed 500 mg/m^2 given IV every 21 days until progression of disease, unacceptable toxicity, or another withdrawal criterion is met.

    Reporting group values
    		 Pemetrexed + Cisplatin + Cixutumumab Pemetrexed + Cisplatin Total
    Number of subjects
    		 87 85 172
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.5 ± 9.87 59.3 ± 9.96 -
    Gender categorical
    Units: Subjects
        Female
    		 33 32 65
        Male
    		 54 53 107
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 1
        Asian
    		 1 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 2 3
        White
    		 81 80 161
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 4 2 6
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 13 24 37
        Not Hispanic or Latino
    		 45 33 78
        Unknown or Not Reported
    		 29 28 57

    End points

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    End points reporting groups
    Reporting group title
    Pemetrexed + Cisplatin + Cixutumumab
    Reporting group description
    		 Induction Treatment: Pemetrexed 500 mg/m^2 plus cisplatin 75 mg/m^2 plus cixutumumab 20 mg/kg given intravenously (IV) on Day 1 of a 21 day cycle for up to 4 cycles. Two additional cycles of cisplatin may be given (6 cycles total) for participants with significant tumor size reduction, after sponsor approval. Maintenance Therapy: Pemetrexed 500 mg/m^2 plus cixutumumab 20 mg/kg given IV every 21 days until progression of disease, unacceptable toxicity, or another withdrawal criterion is met.

    Reporting group title
    Pemetrexed + Cisplatin
    Reporting group description
    		 Induction Treatment: Pemetrexed 500 mg/m^2 plus cisplatin 75 mg/m^2 given IV on Day 1 of a 21 day cycle for up to 4 cycles. Two additional cycles of cisplatin may be given (6 cycles total) for participants with significant tumor size reduction, after sponsor approval. Maintenance Therapy: Pemetrexed 500 mg/m^2 given IV every 21 days until progression of disease, unacceptable toxicity, or another withdrawal criterion is met.

    Primary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS)
    End point description
    PFS was defined as the time from date of randomization until the date of disease progression, or death from any cause, whichever was first. Disease progression was assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, and/or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions. Participants without documentation for disease progression or death were censored at the date of last tumor assessment. The PFS was estimated following the Kaplan-Meier method.
    End point type
    Primary
    End point timeframe
    Randomization Date to Disease Progression or Death From Any Cause Up to 18.3 Months
    End point values
    		 Pemetrexed + Cisplatin + Cixutumumab Pemetrexed + Cisplatin
    Number of subjects analysed
    87 [1]
    85 [2]
    Units: months
        median (confidence interval 95%)
    5.45 (3.88 to 6.05)
    5.22 (4.24 to 6.74)
    Notes
    [1] - All randomized participants. 20 participants censored.
    [2] - All randomized participants. 21 participants censored.
    Statistical analysis title
    		 Statistical Analysis for PFS
    Comparison groups
    Pemetrexed + Cisplatin + Cixutumumab v Pemetrexed + Cisplatin
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.848
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.73
         upper limit
    		 1.47

    Secondary: Percentage of Participants Achieving an Objective Response Rate (ORR)

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    End point title
    		 Percentage of Participants Achieving an Objective Response Rate (ORR)
    End point description
    The ORR is the percentage of all participants with Partial Response (PR) or Complete Response (CR) according to RECIST v1.1. Disease progression was defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, and/or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions. ORR is confirmed best overall tumor response of CR and PR. CR was defined as the disappearance of all target and non-target lesions; PR defined as a >30% decrease in the sum of the longest diameters (LD) of the target lesions, taking as reference the baseline sum of the LD.
    End point type
    Secondary
    End point timeframe
    Randomization Date to Disease Progression Up to 18.3 Months
    End point values
    		 Pemetrexed + Cisplatin + Cixutumumab Pemetrexed + Cisplatin
    Number of subjects analysed
    87 [3]
    85 [4]
    Units: percentage of participants
        number (confidence interval 95%)
    37.9 (27.7 to 49)
    30.6 (21 to 41.5)
    Notes
    [3] - All randomized participants.
    [4] - All randomized participants.
    Statistical analysis title
    		 Statistical Analysis for ORR
    Comparison groups
    Pemetrexed + Cisplatin v Pemetrexed + Cisplatin + Cixutumumab
    Number of subjects included in analysis
    172
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.338
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival is defined as the time from the date of randomization to the date of death from any cause. If the participant is alive at the end of the follow-up period or is lost to follow-up, OS will be censored on the last date the participant is known to be alive. OS was estimated using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Randomization Date to Death From Any Cause Up to 20 Months
    End point values
    		 Pemetrexed + Cisplatin + Cixutumumab Pemetrexed + Cisplatin
    Number of subjects analysed
    87 [5]
    85 [6]
    Units: months
        median (confidence interval 95%)
    10.68 (8.74 to 9999)
    10.38 (7.43 to 14.39)
    Notes
    [5] - Upper limit was not estimable due to data had insufficient events. 47 participants censored.
    [6] - All randomized participants. 39 participants censored.
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    DOR is measured by the time measurement criteria are first met for CR/PR until the first date that the criteria for PD is met, or death is objectively documented. DOR was estimated using the Kaplan-Meier method. Disease progression was assessed via RECIST version 1.1, and defined as at least a 20% increase in the sum of the longest recorded since the baseline measurements, and/or the appearance of one or more new lesion(s), and/or unequivocal progression of existing non-target lesions.
    End point type
    Secondary
    End point timeframe
    Time from Response to Disease Progression or Death from Any Cause Up to 20 Months
    End point values
    		 Pemetrexed + Cisplatin + Cixutumumab Pemetrexed + Cisplatin
    Number of subjects analysed
    23 [7]
    18 [8]
    Units: months
        median (confidence interval 95%)
    4.9 (4.17 to 6.28)
    3.91 (2.92 to 6.41)
    Notes
    [7] - All randomized participants. 10 participants censored.
    [8] - All randomized participants. 8 participants censored.
    No statistical analyses for this end point

    Secondary: Time to Progressive Disease (TTPS)

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    End point title
    		 Time to Progressive Disease (TTPS)
    End point description
    TTPS was defined as the time from the date of randomization until the date of disease progression. Disease progression was assessed via RECIST version 1.1, and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, and/or the appearance of one or more new lesion(s), and/or unequivocal progression of existing non-target lesions. TTPS was estimated using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Randomization Date to disease progression Up to 18.3 Months
    End point values
    		 Pemetrexed + Cisplatin + Cixutumumab Pemetrexed + Cisplatin
    Number of subjects analysed
    87 [9]
    85 [10]
    Units: months
        median (confidence interval 95%)
    6.05 (5.32 to 7.79)
    6.05 (4.93 to 7.89)
    Notes
    [9] - All randomized participants. 39 participants censored.
    [10] - All randomized participants. 36 participants censored.
    No statistical analyses for this end point

    Secondary: Time to Worsening of Symptoms as Measured by Lung Cancer Symptom Scale (LCSS) Score

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    End point title
    		 Time to Worsening of Symptoms as Measured by Lung Cancer Symptom Scale (LCSS) Score
    End point description
    TTPS was defined as the time from the date of randomization until the date of worsening of symptoms as measured by Lung Cancer Symptom Scale (LCSS) score. Symptomatic progression was defined as an increase (worsening) of the Average Symptomatic Burden Index (ASBI) that is, the mean of the six major lung cancer specific symptom scores of the LCSS patient scale - ranging from 0 to 100 where higher score indicates worst outcome). For each participant, the maximum improvement over baseline score was calculated fore each of the 9 LCSS items, ASBI and LCSS total score. Participants without event are censored at the date of the last LCSS assessment. TTPS was estimated using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Time to worsening of symptoms as measured by LCSS score Up to 18.3 Months
    End point values
    		 Pemetrexed + Cisplatin + Cixutumumab Pemetrexed + Cisplatin
    Number of subjects analysed
    87 [11]
    85 [12]
    Units: months
        median (confidence interval 95%)
    2.14 (1.54 to 2.99)
    4.21 (2.43 to 5.36)
    Notes
    [11] - All randomized participants. 38 participants censored.
    [12] - All randomized participants. 46 participants censored.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With a Change in Tumor Size (CTS)

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    End point title
    		 Percentage of Participants With a Change in Tumor Size (CTS)
    End point description
    CTS was measured by percentage change of tumor size at the end of Cycle 2 comparing to baseline tumor size.
    End point type
    Secondary
    End point timeframe
    Change from baseline measurement to the end of Cycle 2
    End point values
    		 Pemetrexed + Cisplatin + Cixutumumab Pemetrexed + Cisplatin
    Number of subjects analysed
    87 [13]
    85 [14]
    Units: Percentage of Participants
        arithmetic mean (standard deviation)
    -23.88 ± 18.859
    -16.04 ± 26.143
    Notes
    [13] - All randomized participants.
    [14] - All randomized participants.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Cixutumumab, Cycle 1 (First Infusion) and Cycle 4 (Fourth Infusion)

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    End point title
    		 Pharmacokinetics (PK): Maximum Serum Concentration (Cmax) of Cixutumumab, Cycle 1 (First Infusion) and Cycle 4 (Fourth Infusion) [15]
    End point description
    End point type
    Secondary
    End point timeframe
    First Infusion: [Prior to Infusion (of Cycle1): 1, 72, 168, 336 hours(hrs) and 504 hrs (i.e. Prior to Infusion of Cycle 2)] and Fourth Infusion; [Prior to Infusion (of Cycle 4),1,24,72,120,168,240,336 hrs and 504 hrs (i.e. Prior to Infusion of Cycle 5)]
    Notes
    [15] - 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: The secondary objective is to assess PK profile of pemetrexed + cisplatin + cixutumumab arm only.
    End point values
    		 Pemetrexed + Cisplatin + Cixutumumab
    Number of subjects analysed
    71 [16]
    Units: microgram/milliliter (ug/mL)
    geometric mean (geometric coefficient of variation)
        First Infusion (n=71)
    481 ± 33
        Fourth Infusion (n=31)
    556 ± 17
    Notes
    [16] - Participants were randomized to pemetrexed + ciplatin + cixutumumab arm and had evaluable PK data.
    No statistical analyses for this end point

    Secondary: Pharmacodynamics (PD) Markers: Free Insulin-like Growth Factor-I (IGF-I, Total IGF-I, and IGF Binding Proteins (IGFBP-3)

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    End point title
    		 Pharmacodynamics (PD) Markers: Free Insulin-like Growth Factor-I (IGF-I, Total IGF-I, and IGF Binding Proteins (IGFBP-3) [17]
    End point description
    Blood samples for the determination of PD marker concentrations were collected at the specified time points for all participants. Analysis of the following markers include free IGF-I, total IGF-I, and IGFBP-3.
    End point type
    Secondary
    End point timeframe
    Preinfusion, Cycle 2, Cycle 4, Cycle 8, Postinfusion, 30-Day Follow-Up
    Notes
    [17] - 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: The secondary objective is to assess the PD profile of pemetrexed + cisplatin + cixutumumab arm only.
    End point values
    		 Pemetrexed + Cisplatin + Cixutumumab
    Number of subjects analysed
    0 [18]
    Units: Number of Participants
    Notes
    [18] - Zero participants were analyzed due to blood samples were not collected to assess biomarker data.
    No statistical analyses for this end point

    Secondary: Immunogenicity of Cixutumumab

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    End point title
    		 Immunogenicity of Cixutumumab [19]
    End point description
    End point type
    Secondary
    End point timeframe
    Preinfusion, Cycle1(C1): 1, 72, 168, 240, 336 hours(hrs); C2 and C3: 1, 168, 336 hrs; C4: 1, 24,72,120,168, 240, 336, 504 hrs, Postinfusion; 30 Day Follow Up
    Notes
    [19] - 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: The secondary objective is to assess the immunogenicity of pemetrexed + cisplatin + cixutumumab arm only.
    End point values
    		 Pemetrexed + Cisplatin + Cixutumumab
    Number of subjects analysed
    0 [20]
    Units: Number of Participants
    Notes
    [20] - Zero participants were analyzed due to no immunogenicity analysis was done and assay never developed
    No statistical analyses for this end point

    Secondary: PK: Area Under the Concentration Time Curve (AUC[0-inf]) of Cixutumumab, Cycle 1 (i.e. First Infusion)

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    End point title
    		 PK: Area Under the Concentration Time Curve (AUC[0-inf]) of Cixutumumab, Cycle 1 (i.e. First Infusion) [21]
    End point description
    End point type
    Secondary
    End point timeframe
    Prior to Infusion (of Cycle 1), 1, 72, 168, 336 hrs and 504 hrs (i.e. Prior to Infusion of Cycle 2)
    Notes
    [21] - 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: The secondary objective is to assess the PK profile of pemetrexed + cisplatin + cixutumumab arm only.
    End point values
    		 Pemetrexed + Cisplatin + Cixutumumab
    Number of subjects analysed
    57 [22]
    Units: microgram*hour/milliliter (ug*hr/mL)
        geometric mean (geometric coefficient of variation)
    73200 ± 35
    Notes
    [22] - Participants were randomized to pemextrexed + cisplatin + cixutumumab arm and had evaluable PK data.
    No statistical analyses for this end point

    Secondary: PK: Area Under the Concentration Time Curve During 1 Dosing Interval (i.e. 504 hr, AUC(0-tau) of Cixutumumab, Cycle 4 (i.e. Fourth Infusion)

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    End point title
    		 PK: Area Under the Concentration Time Curve During 1 Dosing Interval (i.e. 504 hr, AUC(0-tau) of Cixutumumab, Cycle 4 (i.e. Fourth Infusion) [23]
    End point description
    End point type
    Secondary
    End point timeframe
    Prior to Infusion (of Cycle 4), 1, 24, 72, 120, 168, 240, 336 hrs and 504 hrs (i.e. Prior to Infusion of Cycle 5)
    Notes
    [23] - 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: The secondary objective is to assess the PK profile of pemetrexed + cisplatin + cixutumumab arm only.
    End point values
    		 Pemetrexed + Cisplatin + Cixutumumab
    Number of subjects analysed
    27 [24]
    Units: ug*hr/mL
        geometric mean (geometric coefficient of variation)
    79700 ± 30
    Notes
    [24] - Participants who were randomized to the cixutumumab arm and had evaluable PK data
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Adverse event reporting additional description
    I5A-MC-JAEM
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Pemetrexed + Cisplatin + Cixutumumab
    Reporting group description
    		 -

    Reporting group title
    Pemetrexed + Cisplatin
    Reporting group description
    		 -

    Serious adverse events
    		 Pemetrexed + Cisplatin + Cixutumumab Pemetrexed + Cisplatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 85 (57.65%)
    31 / 81 (38.27%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    metastases to bone
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    tumour pain
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    embolism
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    extremity necrosis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haematoma
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypertension
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypotension
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peripheral arterial occlusive disease
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peripheral artery thrombosis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    venous thrombosis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    osteosynthesis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    fatigue
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    7 / 85 (8.24%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    9 / 9
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    general physical health deterioration
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    malaise
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    mucosal inflammation
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    non-cardiac chest pain
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sudden death
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    hypersensitivity
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    acute respiratory failure
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dyspnoea
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    3 / 81 (3.70%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    epistaxis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemoptysis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    3 / 85 (3.53%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    hypoxia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pleural effusion
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonitis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary embolism
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pulmonary haemorrhage
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    pulmonary oedema
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    respiratory failure
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    confusional state
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    blood bilirubin increased
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    blood creatinine increased
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutrophil count decreased
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    platelet count decreased
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    3 / 85 (3.53%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    white blood cell count decreased
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    atrial fibrillation
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    myocardial infarction
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pericarditis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    cerebral ischaemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    ischaemic stroke
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    nervous system disorder
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peripheral motor neuropathy
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    peripheral sensory neuropathy
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    seizure
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    spinal cord compression
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    syncope
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    transient ischaemic attack
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    6 / 85 (7.06%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    8 / 18
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    febrile neutropenia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    3 / 85 (3.53%)
    5 / 81 (6.17%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 5
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    leukopenia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    neutropenia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    4 / 85 (4.71%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    2 / 2
    1 / 1
    pancytopenia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    thrombocytopenia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    vertigo
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    vestibular disorder
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    blindness
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    colitis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    constipation
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    3 / 85 (3.53%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    haemorrhoidal haemorrhage
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    inguinal hernia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lower gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    nausea
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    5 / 85 (5.88%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    oesophagitis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    stomatitis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    upper gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    7 / 85 (8.24%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    8 / 9
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    cholecystitis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    acute kidney injury
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    5 / 85 (5.88%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    renal failure
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    bone pain
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    compartment syndrome
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    muscular weakness
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    rhabdomyolysis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    dengue fever
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    device related infection
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    empyema
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lobar pneumonia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    lung abscess
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lung infection
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    3 / 81 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    mucosal infection
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    3 / 85 (3.53%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia klebsiella
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia pneumococcal
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    postoperative abscess
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    septic shock
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    4 / 81 (4.94%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 7
         deaths causally related to treatment / all
    0 / 1
    1 / 3
    streptococcal bacteraemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    4 / 85 (4.71%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dehydration
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    4 / 85 (4.71%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyperkalaemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyperuricaemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypoalbuminaemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hypocalcaemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    hyponatraemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pemetrexed + Cisplatin + Cixutumumab Pemetrexed + Cisplatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 85 (97.65%)
    79 / 81 (97.53%)
    Vascular disorders
    hypotension
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    8 / 85 (9.41%)
    1 / 81 (1.23%)
         occurrences all number
    8
    1
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    10 / 85 (11.76%)
    9 / 81 (11.11%)
         occurrences all number
    12
    30
    chest pain
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    5 / 81 (6.17%)
         occurrences all number
    3
    10
    fatigue
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    36 / 85 (42.35%)
    33 / 81 (40.74%)
         occurrences all number
    82
    63
    influenza like illness
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    6 / 81 (7.41%)
         occurrences all number
    1
    7
    mucosal inflammation
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    12 / 85 (14.12%)
    3 / 81 (3.70%)
         occurrences all number
    18
    3
    non-cardiac chest pain
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    3 / 85 (3.53%)
    6 / 81 (7.41%)
         occurrences all number
    4
    6
    oedema peripheral
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    7 / 85 (8.24%)
    13 / 81 (16.05%)
         occurrences all number
    7
    19
    pyrexia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    5 / 85 (5.88%)
    10 / 81 (12.35%)
         occurrences all number
    5
    14
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    13 / 85 (15.29%)
    16 / 81 (19.75%)
         occurrences all number
    21
    20
    dyspnoea
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    14 / 85 (16.47%)
    16 / 81 (19.75%)
         occurrences all number
    21
    26
    epistaxis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    7 / 85 (8.24%)
    0 / 81 (0.00%)
         occurrences all number
    11
    0
    productive cough
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    1 / 85 (1.18%)
    5 / 81 (6.17%)
         occurrences all number
    1
    14
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    3 / 85 (3.53%)
    5 / 81 (6.17%)
         occurrences all number
    3
    6
    depression
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    5 / 85 (5.88%)
    4 / 81 (4.94%)
         occurrences all number
    5
    4
    insomnia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    5 / 85 (5.88%)
    7 / 81 (8.64%)
         occurrences all number
    5
    10
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    8 / 85 (9.41%)
    4 / 81 (4.94%)
         occurrences all number
    11
    6
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    4 / 85 (4.71%)
    5 / 81 (6.17%)
         occurrences all number
    4
    7
    blood creatinine increased
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    12 / 85 (14.12%)
    16 / 81 (19.75%)
         occurrences all number
    18
    20
    neutrophil count decreased
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    9 / 85 (10.59%)
    6 / 81 (7.41%)
         occurrences all number
    24
    10
    platelet count decreased
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    6 / 85 (7.06%)
    9 / 81 (11.11%)
         occurrences all number
    6
    14
    weight decreased
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    17 / 85 (20.00%)
    11 / 81 (13.58%)
         occurrences all number
    28
    13
    white blood cell count decreased
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    5 / 85 (5.88%)
    4 / 81 (4.94%)
         occurrences all number
    10
    6
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    11 / 85 (12.94%)
    5 / 81 (6.17%)
         occurrences all number
    13
    7
    dysgeusia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    7 / 85 (8.24%)
    8 / 81 (9.88%)
         occurrences all number
    9
    10
    paraesthesia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    5 / 81 (6.17%)
         occurrences all number
    3
    5
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    33 / 85 (38.82%)
    36 / 81 (44.44%)
         occurrences all number
    103
    98
    leukopenia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    6 / 85 (7.06%)
    5 / 81 (6.17%)
         occurrences all number
    12
    27
    neutropenia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    12 / 85 (14.12%)
    17 / 81 (20.99%)
         occurrences all number
    29
    35
    thrombocytopenia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    8 / 85 (9.41%)
    5 / 81 (6.17%)
         occurrences all number
    31
    9
    Ear and labyrinth disorders
    vertigo
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    9 / 85 (10.59%)
    4 / 81 (4.94%)
         occurrences all number
    11
    4
    Eye disorders
    lacrimation increased
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    8 / 85 (9.41%)
    7 / 81 (8.64%)
         occurrences all number
    8
    10
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    4 / 85 (4.71%)
    11 / 81 (13.58%)
         occurrences all number
    6
    15
    constipation
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    27 / 85 (31.76%)
    19 / 81 (23.46%)
         occurrences all number
    39
    28
    diarrhoea
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    19 / 85 (22.35%)
    16 / 81 (19.75%)
         occurrences all number
    29
    21
    dyspepsia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    5 / 85 (5.88%)
    3 / 81 (3.70%)
         occurrences all number
    5
    4
    dysphagia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    5 / 85 (5.88%)
    1 / 81 (1.23%)
         occurrences all number
    5
    1
    nausea
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    45 / 85 (52.94%)
    41 / 81 (50.62%)
         occurrences all number
    74
    101
    stomatitis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    14 / 85 (16.47%)
    6 / 81 (7.41%)
         occurrences all number
    24
    8
    vomiting
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    29 / 85 (34.12%)
    28 / 81 (34.57%)
         occurrences all number
    41
    55
    Skin and subcutaneous tissue disorders
    alopecia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    7 / 85 (8.24%)
    3 / 81 (3.70%)
         occurrences all number
    8
    3
    rash
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    7 / 85 (8.24%)
    4 / 81 (4.94%)
         occurrences all number
    7
    5
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    9 / 85 (10.59%)
    10 / 81 (12.35%)
         occurrences all number
    10
    13
    bone pain
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    5 / 81 (6.17%)
         occurrences all number
    3
    5
    pain in extremity
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    5 / 85 (5.88%)
    2 / 81 (2.47%)
         occurrences all number
    6
    2
    Infections and infestations
    conjunctivitis
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    3 / 85 (3.53%)
    5 / 81 (6.17%)
         occurrences all number
    5
    6
    upper respiratory tract infection
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    2 / 85 (2.35%)
    6 / 81 (7.41%)
         occurrences all number
    2
    7
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    24 / 85 (28.24%)
    27 / 81 (33.33%)
         occurrences all number
    36
    32
    dehydration
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    10 / 85 (11.76%)
    6 / 81 (7.41%)
         occurrences all number
    13
    8
    hyperglycaemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    43 / 85 (50.59%)
    16 / 81 (19.75%)
         occurrences all number
    156
    45
    hyperkalaemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    5 / 85 (5.88%)
    2 / 81 (2.47%)
         occurrences all number
    8
    3
    hypocalcaemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    5 / 85 (5.88%)
    1 / 81 (1.23%)
         occurrences all number
    7
    1
    hypokalaemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    6 / 85 (7.06%)
    4 / 81 (4.94%)
         occurrences all number
    7
    4
    hypomagnesaemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    9 / 85 (10.59%)
    6 / 81 (7.41%)
         occurrences all number
    13
    6
    hyponatraemia
    alternative dictionary used: MedDRA 14.1
         subjects affected / exposed
    5 / 85 (5.88%)
    4 / 81 (4.94%)
         occurrences all number
    5
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Apr 2011
    The changes made to the protocol were as follows: clarification of inclusion and exclusion criteria clarification of the discontinuation of patients clarification of treatment administration clarification of hyperglycemia assessments clarification of the definition of time to progression disease addition of an interim analysis for safety, after 50 patients complete 2 cycles additional hematology/chemistry assessments during induction (Cycles 1-4) to comply with cisplatin label specification that physical exams will include neurologic assessments to comply with the cisplatin label addition of sampling windows to pharmacokinetics sampling table
    22 Nov 2011
    The changes to the protocol were as follows: inclusion of an independent data assessment committee (IDAC) and clarification of the roles of data assessment committee and IDAC modification of glucose inclusion critera and criteria for starting and stopping daily testing adding an option to extend cisplatin therapy through Cycle 6 for qualifying participants (after Sponsor consultation) and corresponding addition of weekly hematology and -chemistry for these participants modification of chemistry sampling in Cycle 1 for all participants -update of compound background information to be consistent with the most recent IB removal of requirement for full local chemistry panel at each central chemistry time point clarification of use and interpretation of central versus local laboratory chemistry data addition of fasting requirements (minimum of 4 hours) prior each chemistry or glucose assessment
    09 Mar 2012
    The changes to the protocol were as follows: The level of acceptable efficacy has now been reestimated to be at least 7.16 months. 
    11 Apr 2012
    The changes to the protocol were as follows: The protocol has been updated to include drug product at a concentration of 15 mg/mL (750 mg/50 mL).
    19 Feb 2013
    The changes to the protocol were as follows: Addition of the extension period 

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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