Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43862   clinical trials with a EudraCT protocol, of which   7285   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A Phase 1/Randomized Phase 2 Study to Evaluate LY2603618 in Combination with Pemetrexed and Cisplatin in Patients with Stage IV Non-small Cell Lung Cancer

    Summary
    EudraCT number
    		 2010-020408-31
    Trial protocol
    		 DE  
    Global end of trial date
    04 Sep 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Jan 2018
    First version publication date
    05 Jan 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    I2I-MC-JMMG
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01139775
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 13797
    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-CTLILLY,
    Scientific contact
    Available Mon - Fri 9 AM - 5 PM EST, Eli Lilly and Company, +1 877-285-4559,
    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
    04 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective of the Phase 1 part determination of the recommended Phase 2 dose of LY2603618. Primary objective of the Phase 2 part are Determination if the progression-free survival (PFS) time, from the date of randomization to induction therapy, is improved for participants with Stage IV nonsquamous NSCLC when LY2603618 is added to the first-line therapy of 4 cycles of pemetrexed and cisplatin followed by maintenance therapy of pemetrexed with or without LY2603618 Due to the dosing regimen changes, subgroup analysis on participants who were treated per JMMG Amendemnt (c) will be performed for 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
    11 Feb 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 43
    Country: Number of subjects enrolled
    Germany: 33
    Worldwide total number of subjects
    76
    EEA total number of subjects
    76
    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)
    59
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 No Text Entered

    Pre-assignment
    Screening details
    		 No Text Entered

    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
    		 Phase 1: Pemetrexed + Cisplatin + LY2603618
    Arm description
    		 Cycles 1-2 (21-day cycle): Day 1: pemetrexed 500 milligrams per meter square (mg/m^2) + cisplatin 75 mg/m^2 Day 2: LY2603618 at 130-275 milligrams (mg) After 2 cycles, participants may continue on study drug until disease progression, unacceptable toxicity, or other 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 infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously as a continuous 10-minute infusion

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously as a continuous 1-hour infusion

    Investigational medicinal product name
    LY2603618
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously as a continuous 1-hour infusion

    Arm title
    		 Phase 2: Pemetrexed + Cisplatin + LY2603618
    Arm description
    		 Cycles 1-4 (21-day cycle): Before 25 Oct 2012: Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 Day 2: LY2603618 dose from phase 1 portion of trial After 25 Oct 2012: Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 After 4 cycles, participants may continue on maintenance therapy until disease progression, unacceptable toxicity, or other withdrawal criterion is met. Maintenance Therapy Experimental Arm (every 21 days): Before 25 Oct 2012: Day 1: pemetrexed 500 mg/m^2 Day 2: LY2603618 dose determined from phase 1 After 25 Oct 2012: Day 1: pemetrexed 500 mg/m^2 If, as of 25 Oct 2012, participant was in maintenance therapy and randomized to the experimental arm, the participant is eligible to continue with pemetrexed (Day 1)/LY2603618 (Day 2) therapy if the investigator deems it is in the best interest of the participant and the participant consents.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously as a continuous 10-minute infusion

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously as a continuous 1-hour infusion

    Investigational medicinal product name
    LY2603618
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered intravenously as a continuous 1-hour infusion

    Arm title
    		 Phase 2: Pemetrexed + Cisplatin
    Arm description
    		 Cycle 1-4 (21-day cycle) Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 After 4 cycles, participants may continue on maintenance therapy until disease progression, unacceptable toxicity, or other withdrawal criterion is met. Maintenance Therapy Comparator Arm: Phase 2 (every 21 days): Day 1: pemetrexed 500 mg/m^2
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cycles 1-4 (21-day cycle): Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 After 4 cycles, participants may have continued on maintenance therapy until disease progression, unacceptable toxicity, or other withdrawal criterion was met. Maintenance therapy (every 21 days): Day 1: pemetrexed 500 mg/m^2 Pemetrexed was administered IV over 10 minutes, and cisplatin was administered IV over 1 hour.

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin 75 milligrams per meter squared

    Number of subjects in period 1
    		Phase 1: Pemetrexed + Cisplatin + LY2603618 Phase 2: Pemetrexed + Cisplatin + LY2603618 Phase 2: Pemetrexed + Cisplatin
    Started
    14
    39
    23
    Received at least one dose of study drug
    14
    39
    22
    Completed
    13
    26
    17
    Not completed
    1
    13
    6
         Consent withdrawn by subject
    1
    -
    2
         Physician decision
    -
    2
    2
         Adverse event, non-fatal
    -
    6
    2
         Protocol deviation
    -
    5
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Phase 1: Pemetrexed + Cisplatin + LY2603618
    Reporting group description
    		 Cycles 1-2 (21-day cycle): Day 1: pemetrexed 500 milligrams per meter square (mg/m^2) + cisplatin 75 mg/m^2 Day 2: LY2603618 at 130-275 milligrams (mg) After 2 cycles, participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met.

    Reporting group title
    Phase 2: Pemetrexed + Cisplatin + LY2603618
    Reporting group description
    		 Cycles 1-4 (21-day cycle): Before 25 Oct 2012: Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 Day 2: LY2603618 dose from phase 1 portion of trial After 25 Oct 2012: Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 After 4 cycles, participants may continue on maintenance therapy until disease progression, unacceptable toxicity, or other withdrawal criterion is met. Maintenance Therapy Experimental Arm (every 21 days): Before 25 Oct 2012: Day 1: pemetrexed 500 mg/m^2 Day 2: LY2603618 dose determined from phase 1 After 25 Oct 2012: Day 1: pemetrexed 500 mg/m^2 If, as of 25 Oct 2012, participant was in maintenance therapy and randomized to the experimental arm, the participant is eligible to continue with pemetrexed (Day 1)/LY2603618 (Day 2) therapy if the investigator deems it is in the best interest of the participant and the participant consents.

    Reporting group title
    Phase 2: Pemetrexed + Cisplatin
    Reporting group description
    		 Cycle 1-4 (21-day cycle) Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 After 4 cycles, participants may continue on maintenance therapy until disease progression, unacceptable toxicity, or other withdrawal criterion is met. Maintenance Therapy Comparator Arm: Phase 2 (every 21 days): Day 1: pemetrexed 500 mg/m^2

    Reporting group values
    		 Phase 1: Pemetrexed + Cisplatin + LY2603618 Phase 2: Pemetrexed + Cisplatin + LY2603618 Phase 2: Pemetrexed + Cisplatin Total
    Number of subjects
    		 14 39 23 76
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 57.9 ± 11.4 57.9 ± 10.1 56.4 ± 9.8 -
    Gender categorical
    Units: Subjects
        Female
    		 7 15 8 30
        Male
    		 7 24 15 46
    Region of Enrollment
    Units: Subjects
        Spain
    		 7 24 12 43
        Germany
    		 7 15 11 33
    Initial Pathological Diagnosis
    Units: Subjects
        Adenocarcinoma, Bronchiolalveolar
    		 0 0 1 1
        Adenocarcinoma, Colon
    		 1 0 0 1
        Adenocarcinoma, Lung
    		 8 38 19 65
        Adenocarcinoma, Moderately Diff., Lung
    		 0 0 1 1
        Carcinoma, Ampulla of Vater
    		 1 0 0 1
        Carcinoma, Breast
    		 1 0 0 1
        Carcinoma, Large Cell, Lung
    		 0 0 1 1
        Carcinoma, Lung
    		 0 1 0 1
        Carcinoma, Non-small Cell, Poorly Diff, Lung
    		 1 0 0 1
        Carcinoma, Pancreas
    		 1 0 0 1
        Mesothelioma, Malignum
    		 1 0 0 1
        Pleuritis Carcinomatosa
    		 0 0 1 1
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    Measure Description: Eastern Cooperative Oncology Group (ECOG) Performance Status classifies participants according to their functional impairment. Scores range from 0 (Fully Active) to 5 (Death) as follows: 0 - Fully Active; 1 - Ambulatory, Restricted Strenuous Activity; 2 - Ambulatory, No Work Activities; 3 - Partially Confined to Bed, Limited Self Care; 4 - Completely Disabled; and 5 - Dead.
    Units: Subjects
        ECOG Status 0
    		 11 9 7 27
        ECOG Status 1
    		 3 30 15 48
        Missing
    		 0 0 1 1
    Race/Ethnicity
    Units: Subjects
        White
    		 14 39 23 76

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Phase 1: Pemetrexed + Cisplatin + LY2603618
    Reporting group description
    		 Cycles 1-2 (21-day cycle): Day 1: pemetrexed 500 milligrams per meter square (mg/m^2) + cisplatin 75 mg/m^2 Day 2: LY2603618 at 130-275 milligrams (mg) After 2 cycles, participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met.

    Reporting group title
    Phase 2: Pemetrexed + Cisplatin + LY2603618
    Reporting group description
    		 Cycles 1-4 (21-day cycle): Before 25 Oct 2012: Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 Day 2: LY2603618 dose from phase 1 portion of trial After 25 Oct 2012: Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 After 4 cycles, participants may continue on maintenance therapy until disease progression, unacceptable toxicity, or other withdrawal criterion is met. Maintenance Therapy Experimental Arm (every 21 days): Before 25 Oct 2012: Day 1: pemetrexed 500 mg/m^2 Day 2: LY2603618 dose determined from phase 1 After 25 Oct 2012: Day 1: pemetrexed 500 mg/m^2 If, as of 25 Oct 2012, participant was in maintenance therapy and randomized to the experimental arm, the participant is eligible to continue with pemetrexed (Day 1)/LY2603618 (Day 2) therapy if the investigator deems it is in the best interest of the participant and the participant consents.

    Reporting group title
    Phase 2: Pemetrexed + Cisplatin
    Reporting group description
    		 Cycle 1-4 (21-day cycle) Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2 After 4 cycles, participants may continue on maintenance therapy until disease progression, unacceptable toxicity, or other withdrawal criterion is met. Maintenance Therapy Comparator Arm: Phase 2 (every 21 days): Day 1: pemetrexed 500 mg/m^2

    Primary: Phase 2: Progression-Free Survival Time

    		 Close Top of page
    End point title
    		 Phase 2: Progression-Free Survival Time [1]
    End point description
    Progression-free survival (PFS) time is defined as the time from the date of randomization to the first date of documented objective progressive disease (PD) or death from any cause. For participants who were not known to have had objective PD as of the data inclusion cut-off date for a particular analysis, PFS was censored at the date of the last objective progression-free disease assessments. For participants who took any subsequent systemic anticancer therapy prior to progression, PFS was censored at the date of the last objective progression-free disease assessment prior to the start date of any subsequent systemic anticancer therapy. PFS time was summarized using Kaplan-Meier estimates.
    End point type
    Primary
    End point timeframe
    Randomization up to first date of PD or death from any cause (up to 6 months after the last participant entered treatment)
    Notes
    [1] - 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 for progression-free survival time for phase 2 participants only and phase 1 participants were not included.
    End point values
    		 Phase 2: Pemetrexed + Cisplatin + LY2603618 Phase 2: Pemetrexed + Cisplatin
    Number of subjects analysed
    39
    23 [2]
    Units: months
        median (confidence interval 90%)
    4.7 (4.2 to 7.1)
    1.5 (1.3 to 2.9)
    Notes
    [2] - All randomized Phase 2 participants.
    Statistical analysis title
    		 Phase 2: Progression-Free Survival Time
    Comparison groups
    Phase 2: Pemetrexed + Cisplatin + LY2603618 v Phase 2: Pemetrexed + Cisplatin
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.96 [4]
    Method
    		 Bayesian Posterior Probability
    Confidence interval
    Notes
    [3] - The analysis for comparing progression-free survival time between the treatment arms used a Bayesian Augmented Control model with a hierarchical random-effects distribution on treatment effects. The final model incorporated historical data from a completed Phase 3 study (NCT00789373) to augment the prospective control arm data.
    [4] - Inference about survival was made using a Bayesian posterior probability. Pemetrexed + cisplatin + LY2603618 was considered superior to pemetrexed + cisplatin if the posterior probability of superiority exceeded 0.85.

    Primary: Phase 1: Recommended Phase 2 Dose of LY2603618

    		 Close Top of page
    End point title
    		 Phase 1: Recommended Phase 2 Dose of LY2603618 [5] [6]
    End point description
    The recommended Phase 2 dose for LY2603618 when administered approximately 24 hours after pemetrexed and cisplatin was based on the maximum tolerated dose (MTD) and achievement of predefined LY2603618 plasma systemic exposures targets (area under the LY2603618 plasma concentration versus time curve from time zero to infinity [AUC(0-∞)] >21,000 nanogram*hour/milliliter [ng*h/mL] and maximum LY2603618 plasma concentration [Cmax] >2000 nanograms/milliliter [ng/mL]).
    End point type
    Primary
    End point timeframe
    Time of first dose to last dose
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistical analysis was not provided for this endpoint.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was for recommended phase 2 dose of LY2603618 for phase 1 participants only and phase 2 participants were not included.
    End point values
    		 Phase 1: Pemetrexed + Cisplatin + LY2603618
    Number of subjects analysed
    14 [7]
    Units: milligrams
    275
    Notes
    [7] - Phase 1 participants who received at least 1 dose of any of the study drugs.
    No statistical analyses for this end point

    Secondary: Phase 2: Overall Survival

    		 Close Top of page
    End point title
    		 Phase 2: Overall Survival [8]
    End point description
    Overall survival (OS) time is defined as the time from the date of randomization to the date of death from any cause. For participants not known to have died as of the data cut-off date, OS time was censored at the last contact date the participant was known to be alive prior to the data cut-off date. OS was summarized using Kaplan-Meier estimates.
    End point type
    Secondary
    End point timeframe
    Randomization to the date of death from any cause through the time of study discontinuation (approximately 12 months after last participant was randomized)
    Notes
    [8] - 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 for overall survival for phase 2 participants only and phase 1 participants were not included.
    End point values
    		 Phase 2: Pemetrexed + Cisplatin + LY2603618 Phase 2: Pemetrexed + Cisplatin
    Number of subjects analysed
    39 [9]
    23 [10]
    Units: months
        median (confidence interval 90%)
    12.9 (9.3 to 9999)
    6.6 (4.2 to 19.4)
    Notes
    [9] - The upper bound of the 90% confidence interval was not calculable.
    [10] - All randomized Phase 2 participants.
    Statistical analysis title
    		 Phase 2: Overall Survival
    Comparison groups
    Phase 2: Pemetrexed + Cisplatin + LY2603618 v Phase 2: Pemetrexed + Cisplatin
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2294 [11]
    Method
    		 Logrank
    Confidence interval
    Notes
    [11] - The test of treatment effect was conducted at a 2-sided alpha level of 0.10.

    Secondary: Phase 2: Overall Tumor Response Rate: Percentage of Participants Who Achieved a Confirmed Best Response of Completed Response (CR) or Partial Response (PR)

    		 Close Top of page
    End point title
    		 Phase 2: Overall Tumor Response Rate: Percentage of Participants Who Achieved a Confirmed Best Response of Completed Response (CR) or Partial Response (PR) [12]
    End point description
    Overall response rate is the best response of CR or PR as classified by the investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST, v1.1) guidelines. CR is defined as the disappearance of all target and non-target lesions, normalization of tumor marker level of non-target lesions, and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeter (mm). PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with at least 1 measurable lesion, multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Randomization until date of disease progression (up to 6 months after the last participant was randomized)
    Notes
    [12] - 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 for overall tumor response rate for phase 2 arms and phase 1 participants were not included.
    End point values
    		 Phase 2: Pemetrexed + Cisplatin + LY2603618 Phase 2: Pemetrexed + Cisplatin
    Number of subjects analysed
    39
    23 [13]
    Units: percentage of participants
        number (confidence interval 90%)
    43.6 (28 to 60)
    21.7 (7 to 44)
    Notes
    [13] - All randomized Phase 2 participants.
    Statistical analysis title
    		 Phase 2: Overall Tumor Response Rate: Percentage o
    Comparison groups
    Phase 2: Pemetrexed + Cisplatin + LY2603618 v Phase 2: Pemetrexed + Cisplatin
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0824 [14]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [14] - The test of treatment effect was conducted at a 2-sided alpha level of 0.10.

    Secondary: Phase 2: Change in Tumor Size

    		 Close Top of page
    End point title
    		 Phase 2: Change in Tumor Size [15]
    End point description
    Change in tumor size was based on tumor measurements collected according to RECIST, v1.1 guidelines. Tumor size is the sum of the tumor measurements (longest diameters) of target lesions at each tumor evaluation. Change in tumor size was defined as the change in log tumor size from baseline evaluation to the evaluation at the end of Cycle 2. Analysis Population Description: Participants with measureable disease (target lesions) at baseline who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, end of Cycle 2
    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: This endpoint was tumor size for phase 2 participants only and phase 1 participants were not included.
    End point values
    		 Phase 2: Pemetrexed + Cisplatin + LY2603618 Phase 2: Pemetrexed + Cisplatin
    Number of subjects analysed
    39
    22
    Units: centimeters
        arithmetic mean (standard deviation)
    -0.3 ± 0.541
    -0.14 ± 0.277
    Statistical analysis title
    		 Phase 2: Change in Tumor Size
    Comparison groups
    Phase 2: Pemetrexed + Cisplatin + LY2603618 v Phase 2: Pemetrexed + Cisplatin
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4924 [16]
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [16] - The test of treatment effect was conducted at a 2-sided alpha level of 0.10.

    Secondary: Phase 1: Pharmacokinetic: Maximum Plasma Concentration (Cmax) (LY2603618)

    		 Close Top of page
    End point title
    		 Phase 1: Pharmacokinetic: Maximum Plasma Concentration (Cmax) (LY2603618) [17]
    End point description
    Cmax is reported for each LY2603618 dose level on Cycle 1 /Day 2 and Cycle 2 /Day 2. The number of pharmacokinetic observations (n) used in the analysis is presented for each dose level and time point. Analysis Population Description: Phase 1 participants who received at least 1 dose of LY2603618 and had samples collected for pharmacokinetic analysis.
    End point type
    Secondary
    End point timeframe
    Cycle 1/Day 2 - immediately prior to end of LY2603618 infusion, and 1, 3, 6, 24, 48, 72, and 144 hours postdose; Cycle 2/Day 2 - predose, immediately prior to end of LY2603618 infusion, and 1, 3, 6, 24, 48, 72, and 144 hours postdose
    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: This endpoint was maximum plasma concentration of LY2603618 in the phase 1 arm only and phase 2 participants were not included.
    End point values
    		 Phase 1: Pemetrexed + Cisplatin + LY2603618
    Number of subjects analysed
    13 [18]
    Units: nanograms/milliliters
    geometric mean (geometric coefficient of variation)
        130 mg, Cycle 1/Day 2 (n=3)
    1810 ± 14
        130 mg, Cycle 2/Day 2 (n=3)
    1730 ± 43
        185 mg, Cycle 1/Day 2 (n=3)
    2200 ± 33
        185 mg, Cycle 2/Day 2 (n=3)
    2190 ± 58
        240 mg, Cycle 1/Day 2 (n=3)
    3470 ± 27
        240 mg, Cycle 2/Day 2 (n=3)
    2750 ± 63
        275 mg, Cycle 1/Day 2 (n=3)
    4130 ± 29
        275 mg, Cycle 2/Day 2 (n=4)
    3620 ± 23
    Notes
    [18] - Phase 1 participants who received at least 1 dose of LY2603618 and had samples collected for pharmac
    No statistical analyses for this end point

    Secondary: Phase 1: Pharmacokinetic: Cmax (Pemetrexed and Cisplatin)

    		 Close Top of page
    End point title
    		 Phase 1: Pharmacokinetic: Cmax (Pemetrexed and Cisplatin) [19]
    End point description
    Cmax for pemetrexed and total platinum (t-platinum) from cisplatin is reported. The number of pharmacokinetic observations (n) used in the analysis is presented for each drug. Analysis Population Description: Phase 1 participants who received at least 1 dose of pemetrexed or cisplatin and had samples collected for pharmacokinetic analysis.
    End point type
    Secondary
    End point timeframe
    Pemetrexed: Cycle 1/Day 1 - immediately prior to end of pemetrexed infusion and 1, 2, 6 and 24 hours postdose. Cisplatin: Cycle 1/Day 1 - immediately prior to end of cisplatin infusion and 0.5, 1, 2, 6, 24, 72, 96, and 168 hours postdose.
    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: This endpoint was Cmax of pemetrexed and cisplatin in the phase 1 arm only and phase 2 participants were not included.
    End point values
    		 Phase 1: Pemetrexed + Cisplatin + LY2603618
    Number of subjects analysed
    14
    Units: nanograms/milliliters
    geometric mean (geometric coefficient of variation)
        Pemetrexed (n=14)
    88300 ± 28
        T-platinum from cisplatin (n=14)
    3710 ± 43
    No statistical analyses for this end point

    Secondary: Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618)

    		 Close Top of page
    End point title
    		 Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618) [20]
    End point description
    AUC from time zero to 24 hours (AUC[0-24]), AUC from time zero to the last time point with a measurable concentration (AUC[0-tlast]), and AUC from time zero to infinity (AUC[0-∞]) values are reported for each LY2603618 dose level on Cycle 1 /Day 2 and Cycle 2 /Day 2. The number of pharmacokinetic observations (n) used in the analysis is presented for each dose level and time point. Analysis Population Description: Phase 1 participants who received at least 1 dose of LY2603618 and had samples collected for pharmacokinetic analysis.
    End point type
    Secondary
    End point timeframe
    Cycle 1/Day 2 - immediately prior to end of LY2603618 infusion and 1, 3, 6, 24, 48, 72, and 144 hours postdose; Cycle 2/Day 2 - predose, immediately prior to end of LY2603618 infusion, and 1, 3, 6, 24, 48, 72, and 144 hours postdose
    Notes
    [20] - 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 for Area Under the Plasma Concentration Versus Time Curve of LY2603618 in the Phase 1 arm only and phase 2 participants were not included.
    End point values
    		 Phase 1: Pemetrexed + Cisplatin + LY2603618
    Number of subjects analysed
    13
    Units: nanogram*hour/milliliter
    geometric mean (geometric coefficient of variation)
        130 mg, Cycle 1/Day 2, AUC(0-24) (n=3)
    8700 ± 30
        130 mg, Cycle 2/Day 2, AUC(0-24) (n=3)
    9780 ± 43
        130 mg, Cycle 1/Day 1=2, AUC(0-tlast) (n=3)
    10200 ± 26
        130 mg, Cycle 2/Day 2, AUC(0-tlast) (n=3)
    11300 ± 44
        130 mg, Cycle 1/Day 2, AUC(0-∞) (n=3)
    10200 ± 26
        130 mg, Cycle 2/Day 2, AUC(0-∞) (n=3)
    11300 ± 45
        185 mg, Cycle 1/Day 2, AUC(0-24) (n=3)
    13800 ± 119
        185 mg, Cycle 2/Day 2, AUC(0-24) (n=3)
    12500 ± 170
        185 mg, Cycle 1/Day 2, AUC(0-tlast) (n=3)
    18300 ± 192
        185 mg, Cycle 2/Day 2, AUC(0-tlast) (n=3)
    14800 ± 217
        185 mg, Cycle 1/Day 2, AUC(0-∞) (n=3)
    18400 ± 193
        185 mg, Cycle 2/Day 2, AUC(0-∞) (n=3)
    15700 ± 253
        240 mg, Cycle 1/Day 2, AUC(0-24) (n=3)
    26200 ± 19
        240 mg, Cycle 2/Day 2, AUC(0-24) (n=3)
    22100 ± 31
        240 mg, Cycle 1/Day 2, AUC(0-tlast) (n=3)
    32200 ± 21
        240 mg, Cycle 2/Day 2, AUC(0-tlast) (n=3)
    27300 ± 31
        240 mg, Cycle 1/Day 2, AUC(0-∞) (n=3)
    32300 ± 21
        240 mg, Cycle 2/Day 2, AUC(0-∞) (n=3)
    27500 ± 31
        275 mg, Cycle 1/Day 2, AUC(0-24) (n=4)
    28900 ± 24
        275 mg, Cycle 2/Day 2, AUC(0-24) (n=4)
    23500 ± 31
        275 mg, Cycle 1/Day 2, AUC(0-tlast) (n=4)
    38100 ± 36
        275 mg, Cycle 2/Day 2, AUC(0-tlast) (n=4)
    30800 ± 44
        275 mg, Cycle 1/Day 2, AUC(0-∞) (n=4)
    38300 ± 37
        275 mg, Cycle 2/Day 2, AUC(0-∞) (n=4)
    30900 ± 44
    No statistical analyses for this end point

    Secondary: Phase 1: Pharmacokinetic: AUC (Pemetrexed and Cisplatin)

    		 Close Top of page
    End point title
    		 Phase 1: Pharmacokinetic: AUC (Pemetrexed and Cisplatin) [21]
    End point description
    AUC(0-tlast) and AUC(0-∞) values are reported for pemetrexed and t-platinum from cisplatin. The number of pharmacokinetic observations (n) used in the analysis is presented for each drug. Analysis Population Description: Phase 1 participants who received at least 1 dose of pemetrexed or cisplatin and had samples collected for pharmacokinetic analysis.
    End point type
    Secondary
    End point timeframe
    Pemetrexed: Cycle 1/Day 1 - immediately prior to end of pemetrexed infusion and 1, 2, 6 and 24 hours postdose. Cisplatin: Cycle 1/Day 1 - immediately prior to end of cisplatin infusion and 0.5, 1, 2, 6, 24, 72, 96, and 168 hours postdose.
    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: This endpoint was for Area Under the Concentration Time Curve of pemetrexed and t-platinum from cisplatin in the Phase 1 arm only and phase 2 participants were not included.
    End point values
    		 Phase 1: Pemetrexed + Cisplatin + LY2603618
    Number of subjects analysed
    14
    Units: ng*h/mL
    geometric mean (geometric coefficient of variation)
        Pemetrexed, AUC(0-tlast) (n=14)
    159000 ± 35
        Pemetrexed, AUC (0-∞) (n=14)
    160000 ± 35
        T-platinum from cisplatin, AUC (0-tlast) (n=14)
    163000 ± 26
        T-platinum from cisplatin, AUC (0-∞) (n=14)
    269000 ± 26
    No statistical analyses for this end point

    Secondary: Phase 2: Pharmacokinetic: Cmax (LY2603618)

    		 Close Top of page
    End point title
    		 Phase 2: Pharmacokinetic: Cmax (LY2603618) [22]
    End point description
    Analysis Population Description: Phase 2 participants who received at least 1 dose of LY2603618 and had samples collected for pharmacokinetic analysis.
    End point type
    Secondary
    End point timeframe
    Cycle 1/Day 2 - predose, immediately prior to the end of the LY2603618 infusion, and 2-6, 24-48, and 72-96 hours postdose
    Notes
    [22] - 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 for Maximum Concentration of LY2603618 for the Phase 2 arm only and phase 1 (LY2603618) (and phase 2 pemetrexed and cisplatin) participants were not included.
    End point values
    		 Phase 2: Pemetrexed + Cisplatin + LY2603618
    Number of subjects analysed
    33
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    4130 ± 66
    No statistical analyses for this end point

    Secondary: Phase 2: Pharmacokinetic: AUC (LY2603618)

    		 Close Top of page
    End point title
    		 Phase 2: Pharmacokinetic: AUC (LY2603618) [23]
    End point description
    AUC (0-24), AUC(0-tlast), and AUC(0-∞) values are reported for LY2603618. The number of pharmacokinetic observations (n) used in the analysis is presented. Analysis Population Description: Phase 2 participants who received at least 1 dose of LY2603618 and had samples collected for pharmacokinetic analysis.
    End point type
    Secondary
    End point timeframe
    Cycle 1/Day 2 - predose, immediately prior to the end of the LY2603618 infusion, and 2-6, 24-48, and 72-96 hours postdose
    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: This endpoint was for Area Under the Concentration Time Curve of LY2603618 for the Phase 2 arm only and phase 1 (LY2603618) (and phase 2 pemetrexed and cisplatin) participants were not included.
    End point values
    		 Phase 2: Pemetrexed + Cisplatin + LY2603618
    Number of subjects analysed
    33
    Units: ng*h/mL
    geometric mean (geometric coefficient of variation)
        AUC (0-24) (n=32)
    31400 ± 49
        AUC (0-tlast) (n=32)
    39300 ± 58
        AUC (0-∞) (n=31)
    41100 ± 59
    No statistical analyses for this end point

    Secondary: Phase 2: Change From Baseline to Long-term Follow up in Lung Cancer Symptom Scale (LCSS)

    		 Close Top of page
    End point title
    		 Phase 2: Change From Baseline to Long-term Follow up in Lung Cancer Symptom Scale (LCSS) [24]
    End point description
    Health-related quality of life and participant symptoms were assessed using the LCSS (patient scale). However, improper implementation of questionnaires at the site level reduced the sponsor's ability to accurately evaluate the impacted data. Therefore, the LCSS data should be interpreted with caution. The LCSS is a 9-item questionnaire. Six questions are symptom-specific measures for lung cancer (appetite, fatigue, cough, dyspnea, hemoptysis, and pain), and 3 summation items describe total symptomatic distress, activity status, and overall quality of life. Participant responses were measured using visual analogue scales (VAS) with 100-milliliter (mm) lines. Scores range from 0 (for best outcome) to 100 (for worst outcome). The Average Symptom Burden Index (ASBI) was calculated as the mean of 6 symptom-specific questions from the LCSS. The total LCSS score was calculated as the mean of 9 questions from the LCSS.
    End point type
    Secondary
    End point timeframe
    Randomization to the end of study (approximately 12 months after the last participant entered treatment)
    Notes
    [24] - 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 for the phase 2 arms only; the LCSS was not administered to phase 1 participants.
    End point values
    		 Phase 2: Pemetrexed + Cisplatin + LY2603618 Phase 2: Pemetrexed + Cisplatin
    Number of subjects analysed
    36 [25]
    22 [26]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Total LCSS (n=32, 21)
    -10.7 ± 14.1
    -11.7 ± 15.1
        ASBI (n=34, 21)
    -11.6 ± 13.9
    -12.6 ± 15.4
    Notes
    [25] - All phase 2 participants with baseline (BL) LCSS assessment and at least 1 post-baseline assessment.
    [26] - All phase 2 participants with baseline (BL) LCSS assessment and at least 1 post-baseline assessment.
    No statistical analyses for this end point

    Secondary: Phase 1: Document Any Antitumor Activity Per Radiological Scans and/or Tumor Markers

    		 Close Top of page
    End point title
    		 Phase 1: Document Any Antitumor Activity Per Radiological Scans and/or Tumor Markers [27]
    End point description
    Overall response rate is presented. Overall response rate is defined as the percentage of participants with a best response of CR or PR as classified by the investigators according to RECIST, v1.1 criteria. CR is defined as the disappearance of all target and non-target lesions, normalization of tumor marker level of non-target lesions, and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with at least 1 measurable lesion, multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Baseline through end of Phase 1
    Notes
    [27] - 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 for any antitumor activity for the phase 1 arm and phase 2 participants were not included.
    End point values
    		 Phase 1: Pemetrexed + Cisplatin + LY2603618
    Number of subjects analysed
    14 [28]
    Units: percentage of participants
    arithmetic mean (confidence interval 90%)
        130 mg (N=3)
    0 (0 to 0)
        185 mg (N=3)
    66.7 (9 to 99)
        240 mg (N=4)
    25 (1 to 81)
        275 mg (N=4)
    0 (0 to 0)
    Notes
    [28] - All randomized Phase 1 participants.
    No statistical analyses for this end point

    Secondary: Phase 2: Proportion of Participants Receiving Maintenance Therapy

    		 Close Top of page
    End point title
    		 Phase 2: Proportion of Participants Receiving Maintenance Therapy [29]
    End point description
    Since treatment with LY2603618 was discontinued after 25 October 2012, the proportion of participants receiving maintenance therapy was not analyzed.
    End point type
    Secondary
    End point timeframe
    Cycle 5
    Notes
    [29] - 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 for proportion of participants receiving maintenance therapy for phase 2 arms and phase 1 participants were not included.
    End point values
    		 Phase 2: Pemetrexed + Cisplatin + LY2603618 Phase 2: Pemetrexed + Cisplatin
    Number of subjects analysed
    39 [30]
    23 [31]
    Units: percentage of participants
        number (not applicable)
    0
    0
    Notes
    [30] - No participants analyzed due to treatment discontinuation, maintenance therapy not provided.
    [31] - No participants analyzed due to treatment discontinuation, maintenance therapy not provided.
    No statistical analyses for this end point

    Secondary: Phase 2: Clinical Benefit Rate: Percentage of Participant Who Achieved a Response of Stable Disease (SD), Partial Response (PR), or Complete Response (CR)

    		 Close Top of page
    End point title
    		 Phase 2: Clinical Benefit Rate: Percentage of Participant Who Achieved a Response of Stable Disease (SD), Partial Response (PR), or Complete Response (CR) [32]
    End point description
    Clinical benefit rate is the best response CR, PR, or SD as classified by the investigators according to the RECIST, v1.1 guidelines. CR is defined as the disappearance of all target and non-target lesions, normalization of tumor marker level of non-target lesions, and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameter since treatment started. Clinical benefit rate is calculated as a total number of participants with CR, PR, or SD divided by the total number of participants with at least 1 measurable lesion, multiplied by 100.
    End point type
    Secondary
    End point timeframe
    Randomization until date of disease progression or death (up to 6 months after the last participant was randomized)
    Notes
    [32] - 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 for Clinical Benefit Rate for phase 2 arms and phase 1 participants were not included.
    End point values
    		 Phase 2: Pemetrexed + Cisplatin + LY2603618 Phase 2: Pemetrexed + Cisplatin
    Number of subjects analysed
    39
    23 [33]
    Units: percentage of participants
        number (confidence interval 90%)
    69.2 (52 to 83)
    47.8 (27 to 69)
    Notes
    [33] - All randomized Phase 2 participants.
    Statistical analysis title
    		 Phase 2: Clinical Benefit Rate
    Comparison groups
    Phase 2: Pemetrexed + Cisplatin v Phase 2: Pemetrexed + Cisplatin + LY2603618
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0946 [34]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [34] - The test of treatment effect was conducted at a 2-sided alpha level of 0.10.

    Secondary: Deaths

    		 Close Top of page
    End point title
    		 Deaths
    End point description
    Deaths that occurred during the study are presented. A summary of serious and other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
    End point type
    Secondary
    End point timeframe
    Randomization through 12 months after the last participant was randomized
    End point values
    		 Phase 1: Pemetrexed + Cisplatin + LY2603618 Phase 2: Pemetrexed + Cisplatin + LY2603618 Phase 2: Pemetrexed + Cisplatin
    Number of subjects analysed
    14
    39 [35]
    23
    Units: number of participants
        Total deaths
    0
    21
    15
        Deaths while on treatment
    0
    3
    1
        Death within 30 days of last dose of study drug
    0
    1
    0
        Deaths during follow-up period
    0
    17
    14
    Notes
    [35] - All enrolled participants.
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Adverse event reporting additional description
    I2I-MC-JMMG
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Phase 1
    Reporting group description
    		 -

    Reporting group title
    Phase 2: Pemetrexed + Cisplatin
    Reporting group description
    		 -

    Reporting group title
    Phase 2: LY2603618 + Pemetrexed + Cisplatin
    Reporting group description
    		 -

    Serious adverse events
    		 Phase 1 Phase 2: Pemetrexed + Cisplatin Phase 2: LY2603618 + Pemetrexed + Cisplatin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 14 (7.14%)
    6 / 22 (27.27%)
    16 / 39 (41.03%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    metastases to bone
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    metastatic pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 22 (4.55%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    death
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    pyrexia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 22 (4.55%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    acute respiratory distress syndrome
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 22 (4.55%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pulmonary embolism
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    5 / 39 (12.82%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    respiratory failure
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    confusional state
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Investigations
    blood creatinine increased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    blood urea increased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    femur fracture
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    tibia fracture
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    angina pectoris
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    atrial fibrillation
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    cerebrovascular accident
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    convulsion
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 22 (4.55%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ischaemic stroke
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    syncope
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 22 (4.55%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    neutropenia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ileus
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 22 (4.55%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 22 (4.55%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    vomiting
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 22 (4.55%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    musculoskeletal chest pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 22 (4.55%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    spinal pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    infection
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 22 (4.55%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    urinary tract infection bacterial
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    hyperglycaemia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hypokalaemia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ketoacidosis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1 Phase 2: Pemetrexed + Cisplatin Phase 2: LY2603618 + Pemetrexed + Cisplatin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 14 (100.00%)
    22 / 22 (100.00%)
    38 / 39 (97.44%)
    Vascular disorders
    circulatory collapse
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    0
    haematoma
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 22 (0.00%)
    4 / 39 (10.26%)
         occurrences all number
    2
    0
    4
    hypertension
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 14 (21.43%)
    1 / 22 (4.55%)
    3 / 39 (7.69%)
         occurrences all number
    7
    1
    4
    hypertensive crisis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    1
    0
    2
    hypotension
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 22 (4.55%)
    1 / 39 (2.56%)
         occurrences all number
    2
    1
    1
    phlebitis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 22 (4.55%)
    2 / 39 (5.13%)
         occurrences all number
    0
    1
    2
    Surgical and medical procedures
    catheterisation venous
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    5 / 22 (22.73%)
    17 / 39 (43.59%)
         occurrences all number
    2
    12
    82
    catheter site pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    catheter site related reaction
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    catheter site swelling
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    chest discomfort
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 22 (4.55%)
    0 / 39 (0.00%)
         occurrences all number
    1
    2
    0
    chest pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 22 (9.09%)
    4 / 39 (10.26%)
         occurrences all number
    0
    3
    4
    chills
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    3 / 22 (13.64%)
    1 / 39 (2.56%)
         occurrences all number
    2
    4
    2
    fatigue
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    13 / 14 (92.86%)
    14 / 22 (63.64%)
    14 / 39 (35.90%)
         occurrences all number
    35
    21
    23
    infusion site extravasation
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    2
    infusion site pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    2
    mucosal inflammation
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    4 / 22 (18.18%)
    10 / 39 (25.64%)
         occurrences all number
    2
    7
    22
    oedema
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 14 (21.43%)
    1 / 22 (4.55%)
    4 / 39 (10.26%)
         occurrences all number
    3
    1
    7
    oedema peripheral
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 14 (21.43%)
    3 / 22 (13.64%)
    6 / 39 (15.38%)
         occurrences all number
    3
    3
    10
    pyrexia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    6 / 14 (42.86%)
    9 / 22 (40.91%)
    10 / 39 (25.64%)
         occurrences all number
    8
    10
    19
    Immune system disorders
    hypersensitivity
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    3
    0
    3
    Reproductive system and breast disorders
    menstruation irregular
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed [1]
    0 / 7 (0.00%)
    0 / 8 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 14 (21.43%)
    3 / 22 (13.64%)
    8 / 39 (20.51%)
         occurrences all number
    4
    3
    19
    dysphonia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    4 / 22 (18.18%)
    4 / 39 (10.26%)
         occurrences all number
    0
    4
    4
    dyspnoea
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    7 / 22 (31.82%)
    12 / 39 (30.77%)
         occurrences all number
    0
    9
    16
    epistaxis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    5 / 39 (12.82%)
         occurrences all number
    2
    0
    5
    hiccups
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 22 (9.09%)
    1 / 39 (2.56%)
         occurrences all number
    5
    3
    1
    nasal congestion
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    oropharyngeal pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 22 (4.55%)
    0 / 39 (0.00%)
         occurrences all number
    2
    1
    0
    pleural effusion
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    2
    productive cough
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    4 / 22 (18.18%)
    0 / 39 (0.00%)
         occurrences all number
    0
    4
    0
    rhinitis allergic
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    1
    0
    1
    sneezing
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 22 (9.09%)
    3 / 39 (7.69%)
         occurrences all number
    0
    2
    3
    depression
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 22 (4.55%)
    1 / 39 (2.56%)
         occurrences all number
    2
    1
    1
    insomnia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    5 / 14 (35.71%)
    3 / 22 (13.64%)
    4 / 39 (10.26%)
         occurrences all number
    6
    4
    5
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    1
    0
    4
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    0
    0
    4
    blood creatinine increased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 22 (4.55%)
    3 / 39 (7.69%)
         occurrences all number
    3
    1
    5
    blood urea increased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    4 / 39 (10.26%)
         occurrences all number
    0
    0
    4
    c-reactive protein increased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 22 (4.55%)
    3 / 39 (7.69%)
         occurrences all number
    0
    1
    3
    neutrophil count decreased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 22 (9.09%)
    3 / 39 (7.69%)
         occurrences all number
    6
    5
    4
    platelet count decreased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    3
    0
    8
    weight decreased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 22 (9.09%)
    3 / 39 (7.69%)
         occurrences all number
    0
    3
    4
    white blood cell count decreased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    4
    0
    4
    Injury, poisoning and procedural complications
    contrast media reaction
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    0
    infusion related reaction
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    5
    0
    0
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 22 (4.55%)
    6 / 39 (15.38%)
         occurrences all number
    1
    1
    12
    dysaesthesia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    0
    dysgeusia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 22 (4.55%)
    2 / 39 (5.13%)
         occurrences all number
    2
    1
    2
    headache
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 14 (21.43%)
    2 / 22 (9.09%)
    8 / 39 (20.51%)
         occurrences all number
    5
    2
    17
    hypoaesthesia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 22 (9.09%)
    1 / 39 (2.56%)
         occurrences all number
    0
    3
    1
    neurotoxicity
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    7 / 39 (17.95%)
         occurrences all number
    0
    0
    9
    paraesthesia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 14 (21.43%)
    1 / 22 (4.55%)
    4 / 39 (10.26%)
         occurrences all number
    5
    1
    4
    paresis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    1
    0
    1
    presyncope
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 22 (4.55%)
    1 / 39 (2.56%)
         occurrences all number
    2
    1
    1
    somnolence
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    1
    0
    1
    tremor
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    4
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 14 (21.43%)
    3 / 22 (13.64%)
    7 / 39 (17.95%)
         occurrences all number
    16
    6
    16
    leukocytosis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 22 (9.09%)
    0 / 39 (0.00%)
         occurrences all number
    0
    2
    0
    leukopenia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    5 / 39 (12.82%)
         occurrences all number
    2
    0
    11
    lymphopenia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    neutropenia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    6 / 14 (42.86%)
    4 / 22 (18.18%)
    8 / 39 (20.51%)
         occurrences all number
    13
    7
    11
    thrombocytopenia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 22 (4.55%)
    1 / 39 (2.56%)
         occurrences all number
    10
    1
    1
    thrombocytosis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    ototoxicity
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 22 (4.55%)
    8 / 39 (20.51%)
         occurrences all number
    0
    2
    22
    tinnitus
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 22 (9.09%)
    5 / 39 (12.82%)
         occurrences all number
    4
    2
    7
    vertigo
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 14 (21.43%)
    1 / 22 (4.55%)
    2 / 39 (5.13%)
         occurrences all number
    4
    1
    3
    Eye disorders
    conjunctivitis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    3 / 22 (13.64%)
    2 / 39 (5.13%)
         occurrences all number
    9
    4
    3
    eye oedema
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 22 (4.55%)
    3 / 39 (7.69%)
         occurrences all number
    0
    1
    4
    eyelid oedema
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    lacrimation increased
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 22 (4.55%)
    2 / 39 (5.13%)
         occurrences all number
    1
    1
    2
    papilloedema
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 22 (9.09%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    2
    abdominal pain upper
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 14 (21.43%)
    2 / 22 (9.09%)
    1 / 39 (2.56%)
         occurrences all number
    3
    2
    1
    constipation
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    8 / 22 (36.36%)
    18 / 39 (46.15%)
         occurrences all number
    4
    13
    30
    diarrhoea
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 14 (21.43%)
    4 / 22 (18.18%)
    11 / 39 (28.21%)
         occurrences all number
    5
    6
    17
    dry mouth
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    2
    0
    1
    dyspepsia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 22 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    2
    0
    2
    dysphagia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 22 (4.55%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    1
    flatulence
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    0
    gastritis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    1
    0
    1
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 22 (4.55%)
    1 / 39 (2.56%)
         occurrences all number
    2
    1
    1
    nausea
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    12 / 14 (85.71%)
    15 / 22 (68.18%)
    30 / 39 (76.92%)
         occurrences all number
    44
    27
    106
    toothache
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    vomiting
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    7 / 14 (50.00%)
    6 / 22 (27.27%)
    18 / 39 (46.15%)
         occurrences all number
    13
    9
    42
    Skin and subcutaneous tissue disorders
    alopecia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    4 / 14 (28.57%)
    0 / 22 (0.00%)
    5 / 39 (12.82%)
         occurrences all number
    4
    0
    5
    angioedema
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    dermatitis acneiform
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    dry skin
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 22 (4.55%)
    3 / 39 (7.69%)
         occurrences all number
    2
    2
    3
    eczema
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    3 / 22 (13.64%)
    2 / 39 (5.13%)
         occurrences all number
    0
    3
    2
    erythema
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 22 (4.55%)
    2 / 39 (5.13%)
         occurrences all number
    1
    1
    2
    erythema multiforme
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 22 (4.55%)
    0 / 39 (0.00%)
         occurrences all number
    1
    1
    0
    hyperhidrosis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 22 (4.55%)
    2 / 39 (5.13%)
         occurrences all number
    2
    1
    2
    nail disorder
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    2
    night sweats
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 22 (4.55%)
    0 / 39 (0.00%)
         occurrences all number
    1
    1
    0
    pruritus
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    4 / 22 (18.18%)
    1 / 39 (2.56%)
         occurrences all number
    3
    4
    1
    rash
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 22 (9.09%)
    4 / 39 (10.26%)
         occurrences all number
    3
    2
    4
    skin discolouration
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    0
    skin disorder
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    2
    skin lesion
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    2
    Renal and urinary disorders
    nephrolithiasis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 22 (9.09%)
    2 / 39 (5.13%)
         occurrences all number
    1
    2
    3
    back pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 22 (9.09%)
    3 / 39 (7.69%)
         occurrences all number
    1
    2
    3
    bone pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 22 (9.09%)
    3 / 39 (7.69%)
         occurrences all number
    1
    2
    3
    muscle spasms
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    musculoskeletal chest pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 22 (4.55%)
    5 / 39 (12.82%)
         occurrences all number
    1
    1
    6
    musculoskeletal pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 14 (21.43%)
    4 / 22 (18.18%)
    7 / 39 (17.95%)
         occurrences all number
    3
    6
    11
    osteoarthritis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    pain in extremity
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 22 (4.55%)
    3 / 39 (7.69%)
         occurrences all number
    3
    1
    4
    spinal pain
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    4
    Infections and infestations
    bronchitis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 22 (9.09%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    2
    candida infection
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    2
    eye infection
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    gingivitis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 22 (4.55%)
    0 / 39 (0.00%)
         occurrences all number
    2
    1
    0
    herpes simplex
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    laryngitis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    1 / 39 (2.56%)
         occurrences all number
    1
    0
    2
    nasopharyngitis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 22 (9.09%)
    5 / 39 (12.82%)
         occurrences all number
    1
    2
    5
    paronychia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    2
    pneumonia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    respiratory tract infection
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 22 (4.55%)
    2 / 39 (5.13%)
         occurrences all number
    0
    1
    2
    rhinitis
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 22 (4.55%)
    0 / 39 (0.00%)
         occurrences all number
    2
    1
    0
    upper respiratory tract infection
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    3 / 14 (21.43%)
    1 / 22 (4.55%)
    1 / 39 (2.56%)
         occurrences all number
    3
    1
    1
    urinary tract infection
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 22 (4.55%)
    2 / 39 (5.13%)
         occurrences all number
    0
    1
    2
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    12 / 22 (54.55%)
    14 / 39 (35.90%)
         occurrences all number
    3
    19
    45
    dehydration
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 22 (4.55%)
    0 / 39 (0.00%)
         occurrences all number
    1
    1
    0
    dyslipidaemia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 22 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0
    0
    hyperglycaemia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    2 / 14 (14.29%)
    2 / 22 (9.09%)
    1 / 39 (2.56%)
         occurrences all number
    3
    4
    1
    hypocalcaemia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 22 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    0
    0
    2
    hypokalaemia
    alternative dictionary used: MedDRA 16.1
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 22 (4.55%)
    3 / 39 (7.69%)
         occurrences all number
    2
    1
    3
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly.

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Mar 2012
    Amendment b: Incorporated pemetrexed maintenance therapy into the study design.
    30 Nov 2012
    Amendment d: As a result of the safety findings leading to the halt in enrollment, this amendment incorporated changes to the dosing regimen for participants assigned to the experimental arm.

    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.
    Enrollment was halted on 25 October 2012 due to a numerical imbalance in events of thromboembolic nature between the experimental arm and the control arm.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-Fri Apr 26 15:16:54 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA