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    Clinical Trial Results:
    A Phase 1/Randomized Phase 2 Study to Evaluate LY2603618 in Combination With Gemcitabine in Patients With Pancreatic Cancer

    Summary
    EudraCT number
    		 2008-006209-17
    Trial protocol
    		 DE   SK   PL   IT  
    Global end of trial date
    09 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Mar 2018
    First version publication date
    06 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    I2I-MC-JMMC
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00839332
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 12096
    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
    09 Dec 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of the Phase 1 portion of this study was to determine the dose of LY2603618 that can be safely administered 24 hours after gemcitabine treatment. This dose was then used for the Phase 2 portion of the study. The Phase 2 portion of the study evaluated whether LY2603618, when administered 24 hours after gemcitabine therapy, was an effective treatment for participants with pancreatic cancer
    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
    26 Feb 2009
    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
    United States: 73
    Country: Number of subjects enrolled
    Spain: 35
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Poland: 2
    Worldwide total number of subjects
    149
    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)
    80
    From 65 to 84 years
    68
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 No Text Entered

    Period 1
    Period 1 title
    Phase 1/2 (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: LY2603618 + Gemcitabine
    Arm description
    		 All participants in Phase 1 received LY2603618 in combination with gemcitabine. LY2603618: 70 to 250 milligrams/meter squared (mg/m^2) LY2603618 as a 1-hour continuous intravenous (IV) infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Participants received LY2603618 as part of the dose escalation cohort of Phase 1 (dose of 70, 105, 150, 200, or 250 mg/m^2) or as part of the expansion cohort of Phase 1 (flat dose of 200 or 230 mg). The flat dose cohorts were conducted in parallel. Gemcitabine: 1000 mg/m^2 gemcitabine as a 30-minute continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Participants received gemcitabine 24 hours prior to LY2603618 administration.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LY2603618
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    75 to 250 milligrams/meter squared (mg/m^2) LY2603618 as a 1-hour continuous intravenous (IV) infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression (DP). Participants received LY2603618 as part of the dose escalation cohort (dose of 70, 105, 150, 200, or 250 mg/m^2) or the expansion cohort (flat dose of 200 mg or 230 mg).

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg/m^2 gemcitabine as a 30-minute continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until DP. Participants received gemcitabine 24 hours prior to LY2603618 administration

    Arm title
    		 Phase 2: LY2603618 + Gemcitabine
    Arm description
    		 LY2603618: 230 mg flat dose LY2603618 as a 1-hour continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Gemcitabine: Participants were administered 1000 mg/m^2 gemcitabine as a 30-minute continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Participants received gemcitabine 24 hours prior to LY2603618 administration.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LY2603618
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    230 mg flat dose LY2603618 as a 1-hour continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression.

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg/m^2 gemcitabine as a 30-minute continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Participants received gemcitabine 24 hours prior to LY2603618 administration.

    Arm title
    		 Phase 2: Gemcitabine
    Arm description
    		 Gemcitabine: 1000 mg/m^2 gemcitabine as a 30-minute continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    1000 mg/m^2 gemcitabine as a 30-minute continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression.

    Number of subjects in period 1
    		Phase 1: LY2603618 + Gemcitabine Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Started
    50
    65
    34
    Received at least 1 dose of study drug
    50
    65
    34
    Completed
    0
    0
    0
    Not completed
    50
    65
    34
         Adverse event, serious fatal
    -
    3
    1
         Consent withdrawn by subject
    4
    3
    5
         Physician decision
    2
    4
    1
         Adverse event, non-fatal
    6
    8
    6
         Disease Progression
    38
    46
    21
         Protocol deviation
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1: LY2603618 + Gemcitabine
    Reporting group description
    		 All participants in Phase 1 received LY2603618 in combination with gemcitabine. LY2603618: 70 to 250 milligrams/meter squared (mg/m^2) LY2603618 as a 1-hour continuous intravenous (IV) infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Participants received LY2603618 as part of the dose escalation cohort of Phase 1 (dose of 70, 105, 150, 200, or 250 mg/m^2) or as part of the expansion cohort of Phase 1 (flat dose of 200 or 230 mg). The flat dose cohorts were conducted in parallel. Gemcitabine: 1000 mg/m^2 gemcitabine as a 30-minute continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Participants received gemcitabine 24 hours prior to LY2603618 administration.

    Reporting group title
    Phase 2: LY2603618 + Gemcitabine
    Reporting group description
    		 LY2603618: 230 mg flat dose LY2603618 as a 1-hour continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Gemcitabine: Participants were administered 1000 mg/m^2 gemcitabine as a 30-minute continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Participants received gemcitabine 24 hours prior to LY2603618 administration.

    Reporting group title
    Phase 2: Gemcitabine
    Reporting group description
    		 Gemcitabine: 1000 mg/m^2 gemcitabine as a 30-minute continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression.

    Reporting group values
    		 Phase 1: LY2603618 + Gemcitabine Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine Total
    Number of subjects
    		 50 65 34 149
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 29 35 16 80
        From 65-84 years
    		 21 30 17 68
        85 years and over
    		 0 0 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59 ( 12.2 ) 64.3 ( 8.3 ) 64.4 ( 10.1 ) -
    Gender, Male/Female
    Units:
        Female
    		 24 23 14 61
        Male
    		 26 42 20 88
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 46 62 32 140
        Black or African American
    		 1 2 2 5
        American Indian or Alaska Native
    		 0 1 0 1
        Asian
    		 3 0 0 3
    Region of Enrollment
    Units: Subjects
        United States
    		 32 27 14 73
        Spain
    		 18 12 5 35
        Romania
    		 0 2 1 3
        Germany
    		 0 17 9 26
        Netherlands
    		 0 3 2 5
        Italy
    		 0 3 2 5
        Poland
    		 0 1 1 2
    Initial Pathological Diagnosis
    Units: Subjects
        Adenocarcinoma, Pancreas
    		 10 65 34 109
        Adenocarcinoma, Colon
    		 7 0 0 7
        Carcinoma, Breast
    		 4 0 0 4
        Carcinoma, Non-Small Cell, Lung NOS
    		 3 0 0 3
        Adenocarcinoma, Cervix
    		 2 0 0 2
        Adenocarcinoma, Rectum
    		 2 0 0 2
        Carcinoma, Endometrium
    		 2 0 0 2
        Carcinoma, Infiltrating Ductal, Breast
    		 2 0 0 2
        Carcinoma, Renal Cell
    		 2 0 0 2
        Sarcoma, Leiomyosarcoma, Abdomen (Non-Gist)
    		 2 0 0 2
        Squamous Cell Carcinoma, Head and Neck
    		 2 0 0 2
        Ampulla of Pancreas
    		 1 0 0 1
        Carcinoma, Head and Neck
    		 1 0 0 1
        Carcinoma, Ovarian
    		 1 0 0 1
        Carcinoma, Peritoneal
    		 1 0 0 1
        Carcinoma, Small Cell, Lung
    		 1 0 0 1
        Carcinoma, Transitional Cell, Urothelium
    		 1 0 0 1
        Ewing's Sarcoma
    		 1 0 0 1
        Lymphoma, Non-Hodgkin's Lymphoma
    		 1 0 0 1
        Mesothelioma, Pleural, Malignant
    		 1 0 0 1
        Ovarian Adenocarcinoma
    		 1 0 0 1
        Squamous Cell Carcinoma, Cervix
    		 1 0 0 1
        Tumor
    		 1 0 0 1
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    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
    		 19 28 14 61
        ECOG Status 1
    		 31 31 17 79
        ECOG Status 2
    		 0 6 3 9

    End points

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    End points reporting groups
    Reporting group title
    Phase 1: LY2603618 + Gemcitabine
    Reporting group description
    		 All participants in Phase 1 received LY2603618 in combination with gemcitabine. LY2603618: 70 to 250 milligrams/meter squared (mg/m^2) LY2603618 as a 1-hour continuous intravenous (IV) infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Participants received LY2603618 as part of the dose escalation cohort of Phase 1 (dose of 70, 105, 150, 200, or 250 mg/m^2) or as part of the expansion cohort of Phase 1 (flat dose of 200 or 230 mg). The flat dose cohorts were conducted in parallel. Gemcitabine: 1000 mg/m^2 gemcitabine as a 30-minute continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Participants received gemcitabine 24 hours prior to LY2603618 administration.

    Reporting group title
    Phase 2: LY2603618 + Gemcitabine
    Reporting group description
    		 LY2603618: 230 mg flat dose LY2603618 as a 1-hour continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Gemcitabine: Participants were administered 1000 mg/m^2 gemcitabine as a 30-minute continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Participants received gemcitabine 24 hours prior to LY2603618 administration.

    Reporting group title
    Phase 2: Gemcitabine
    Reporting group description
    		 Gemcitabine: 1000 mg/m^2 gemcitabine as a 30-minute continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression.

    Primary: Phase 1: Determine the recommended Phase 2 dose for LY2603618 when administered after gemcitabine

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    End point title
    		 Phase 1: Determine the recommended Phase 2 dose for LY2603618 when administered after gemcitabine [1] [2]
    End point description
    The recommended Phase 2 dose for LY2603618 when administered approximately 24 hours after gemcitabine was based on the maximum tolerated dose 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-inf)] >21,000 nanogram*hour/milliliter [ng*h/mL] and maximum LY2603618 plasma concentration [Cmax] >2000 nanograms/milliliter [ng/mL]). Population analyzed was all phase 1 participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline through 18 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Statistics are being reported for only phase 1 participants as per the protocol or Statistical Analysis Plan or both.
    [2] - 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: Statistics are being reported for only phase 1 participants as per the protocol or Statistical Analysis Plan or both.
    End point values
    		 Phase 1: LY2603618 + Gemcitabine
    Number of subjects analysed
    50
    Units: milligrams (mg)
        number (not applicable)
    230
    No statistical analyses for this end point

    Primary: Phase 2: Overall Survival (OS)

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    End point title
    		 Phase 2: Overall Survival (OS) [3]
    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 cut-off date. OS was summarized using Kaplan-Meier estimates. Population analyzed was all phase 2 participants who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Phase 2: Baseline to date of death
    Notes
    [3] - 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: Statistics are being reported for only phase 2 participants as per the protocol or Statistical Analysis Plan or both.
    End point values
    		 Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Number of subjects analysed
    65
    34
    Units: months
        median (confidence interval 95%)
    7.8 (5 to 11.1)
    8.3 (5.1 to 14.1)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Phase 2: LY2603618 + Gemcitabine v Phase 2: Gemcitabine
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.333 [4]
    Method
    		 Bayesian Posterior Probability
    Confidence interval
    Notes
    [4] - Inference about survival was made using a Bayesian posterior probability. The combination treatment would have been considered superior to gemcitabine alone if the posterior probability of superiority exceeded 0.8.

    Secondary: Phase 1: Maximum Plasma Concentration (Cmax) of gemcitabine, 2',2'-difluorodeoxyuridine (dFdU), and LY2603618

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    End point title
    		 Phase 1: Maximum Plasma Concentration (Cmax) of gemcitabine, 2',2'-difluorodeoxyuridine (dFdU), and LY2603618 [5]
    End point description
    Plasma samples for pharmacokinetic (PK) analysis were collected following IV infusion of each study drug. However, the dose-normalized PK analysis of gemcitabine and dFdU were not reported because the gemcitabine and dFdU plasma concentration data generated for all participants with PK samples collected in this study were withdrawn (invalidated) as a result of the failure of the Incurred Sample Reanalysis (ISR) for both gemcitabine and dFdU. Therefore, only the LY2603618 plasma Cmax values are reported for each LY2603618 dose level on Cycle (C) 1 /Day (D) 1, Cycle 1 /Day 16, and Cycle 2 /Day 2. The number of PK observations (n) used in the analysis is presented for each dose level and time point. Population analyzed was all phase 1 participants who received at least 1 dose of study drug and had sufficient LY2603618 plasma concentration data to enable determination of the LY2603618 Cmax.
    End point type
    Secondary
    End point timeframe
    Phase 1: LY2603618 - Predose and 0, 1, 3, 6, 24, 48, and 72 hours after the end of infusion on C1 /D2, C1 /D16, and C2 /D2. Gemcitabine - Predose and 0, 10, 30, 60, and 120 minutes after the end of infusion on C1 /D1, C1 /D15, and C2 /D1.
    Notes
    [5] - 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: Statistics are being reported for only phase 1 participants as per the protocol or Statistical Analysis Plan or both.
    End point values
    		 Phase 1: LY2603618 + Gemcitabine
    Number of subjects analysed
    50
    Units: nanograms per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        70 mg/m^2, Cycle 1 /Day 2 (n=2)
    3530 ( 23 )
        70 mg/m^2, Cycle 1 /Day 16 (n=3)
    3360 ( 26 )
        70 mg/m^2, Cycle 2 /Day 2 (n=3)
    3100 ( 12 )
        105 mg/m^2, Cycle 1 /Day 2 (n=3)
    4890 ( 25 )
        105 mg/m^2, Cycle 1 /Day 16 (n=3)
    5170 ( 38 )
        105 mg/m^2, Cycle 2 /Day 2 (n=3)
    5360 ( 23 )
        150 mg/m^2, Cycle 1 /Day 2 (n=7)
    4280 ( 29 )
        150 mg/m^2, Cycle 1 /Day 16 (n=6)
    5040 ( 38 )
        150 mg/m^2, Cycle 2 /Day 2 (n=6)
    4370 ( 38 )
        200 mg/m^2, Cycle 1 /Day 2 (n=11)
    4870 ( 63 )
        200 mg/m^2, Cycle 1 /Day 16 (n=8)
    5360 ( 40 )
        200 mg/m^2, Cycle 2 /Day 2 (n=11)
    5290 ( 40 )
        250 mg/m^2, Cycle 1 /Day 2 (n=5)
    7990 ( 25 )
        250 mg/m^2, Cycle 1 /Day 16 (n=3)
    7990 ( 6 )
        250 mg/m^2, Cycle 2 /Day 2 (n=3)
    5290 ( 35 )
        200 mg (flat dose), Cycle 1 /Day 2 (n=10)
    3440 ( 65 )
        200 mg (flat dose), Cycle 1 /Day 16 (n=6)
    3470 ( 61 )
        200 mg (flat dose), Cycle 2 /Day 2 (n=8)
    3640 ( 45 )
        230 mg (flat dose), Cycle 1 /Day 2 (n=10)
    4820 ( 72 )
        230 mg (flat dose), Cycle 1 /Day 16 (n=6)
    4980 ( 35 )
        230 mg (flat dose), Cycle 2 /Day 2 (n=7)
    3830 ( 26 )
    No statistical analyses for this end point

    Secondary: Phase 1: Area Under the Plasma Concentration versus Time Curve (AUC) of gemcitabine, dFdU, and LY2603618

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    End point title
    		 Phase 1: Area Under the Plasma Concentration versus Time Curve (AUC) of gemcitabine, dFdU, and LY2603618 [6]
    End point description
    Plasma samples for PK analysis were collected following IV infusion of each study drug. However, the dose-normalized PK analysis of gemcitabine and dFdU were not reported because the gemcitabine plasma and dFdU concentration data generated for all pts. with PK samples collected in this study were withdrawn (invalidated) as a result of failure of Incurred Sample Reanalysis (ISR) for both gemcitabine and dFdU. Therefore, only study drug plasma AUC from time zero to 24 hours (AUC[0-24]), AUC from time zero to last time point with measurable concentration (AUC[0-tlast]), and AUC from time zero to infinity (AUC[0-inf]) values are reported for each study drug dose level on Cycle1/Day1, Cycle1/Day16, and Cycle2/Day2. The number of PK observations (n) used in the analysis is presented for each dose level and time point. Population analyzed was all phase 1 pts. who received at least 1 dose of study drug and had sufficient study drug plasma concentration to enable calculation of study drug AUC.
    End point type
    Secondary
    End point timeframe
    Phase 1: LY2603618 - Predose and 0, 1, 3, 6, 24, 48, and 72 hours after the end of infusion on C1 /D2, C1 /D16, and C2 /D2. Gemcitabine - Predose and 0, 10, 30, 60, and 120 minutes after the end of infusion on C1 /D1, C1 /D15, and C2 /D1.
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for only phase 1 participants as per the protocol or Statistical Analysis Plan or both.
    End point values
    		 Phase 1: LY2603618 + Gemcitabine
    Number of subjects analysed
    50
    Units: nanogram*hour/milliliter (ng*h/mL)
    geometric mean (geometric coefficient of variation)
        AUC(0-24), 70 mg/m^2, Cycle 1 /Day 2 (n=2)
    21300 ( 24 )
        AUC(0-24), 70 mg/m^2, Cycle 1 /Day 16 (n=3)
    21200 ( 27 )
        AUC(0-24), 70 mg/m^2, Cycle 2 /Day 2 (n=3)
    19900 ( 24 )
        AUC(0-24), 105 mg/m^2, Cycle 1 /Day 2 (n=3)
    40500 ( 23 )
        AUC(0-24), 105 mg/m^2, Cycle 1 /Day 16 (n=3)
    50100 ( 32 )
        AUC(0-24), 105 mg/m^2, Cycle 2 /Day 2 (n=3)
    49800 ( 4 )
        AUC(0-24), 150 mg/m^2, Cycle 1 /Day 2 (n=7)
    32200 ( 27 )
        AUC(0-24), 150 mg/m^2, Cycle 1 /Day 16 (n=6)
    40000 ( 29 )
        AUC(0-24), 150 mg/m^2, Cycle 2 /Day 2 (n=6)
    31000 ( 42 )
        AUC(0-24), 200 mg/m^2, Cycle 1 /Day 2 (n=10)
    40200 ( 42 )
        AUC(0-24), 200 mg/m^2, Cycle 1 /Day 16 (n=8)
    39800 ( 36 )
        AUC(0-24), 200 mg/m^2, Cycle 2 /Day 2 (n=11)
    44300 ( 39 )
        AUC(0-24), 250 mg/m^2, Cycle 1 /Day 2 (n=5)
    88800 ( 27 )
        AUC(0-24), 250 mg/m^2, Cycle 1 /Day 16 (n=3)
    61000 ( 63 )
        AUC(0-24), 250 mg/m^2, Cycle 2 /Day 2 (n=3)
    40000 ( 112 )
        AUC(0-24), 200 mg (flat), Cycle 1 /Day 2 (n=10)
    22900 ( 77 )
        AUC(0-24), 200 mg (flat), Cycle 1 /Day 16 (n=6)
    28700 ( 63 )
        AUC(0-24), 200 mg (flat), Cycle 2 /Day 2 (n=8)
    23800 ( 62 )
        AUC(0-24), 230 mg (flat), Cycle 1 /Day 2 (n=10)
    32400 ( 38 )
        AUC(0-24), 230 mg (flat), Cycle 1 /Day 16 (n=6)
    32300 ( 22 )
        AUC(0-24), 230 mg (flat), Cycle 2 /Day 2 (n=7)
    32500 ( 24 )
        AUC(0-tlast), 70 mg/m^2, Cycle 1 /Day 2 (n=2)
    24600 ( 28 )
        AUC(0-tlast), 70 mg/m^2, Cycle 1 /Day 16 (n=3)
    27500 ( 21 )
        AUC(0-tlast), 70 mg/m^2, Cycle 2 /Day 2 (n=3)
    25800 ( 29 )
        AUC(0-tlast), 105 mg/m^2, Cycle 1 /Day 2 (n=3)
    65800 ( 53 )
        AUC(0-tlast), 105 mg/m^2, Cycle 1 /Day 16 (n=3)
    75500 ( 46 )
        AUC(0-tlast), 105 mg/m^2, Cycle 2 /Day 2 (n=3)
    79600 ( 19 )
        AUC(0-tlast), 150 mg/m^2, Cycle 1 /Day 2 (n=7)
    41600 ( 31 )
        AUC(0-tlast), 150 mg/m^2, Cycle 1 /Day 16 (n=6)
    52000 ( 38 )
        AUC(0-tlast), 150 mg/m^2, Cycle 2 /Day 2 (n=6)
    39800 ( 45 )
        AUC(0-tlast), 200 mg/m^2, Cycle 1 /Day 2 (n=11)
    44300 ( 85 )
        AUC(0-tlast), 200 mg/m^2, Cycle 1 /Day 16 (n=8)
    55300 ( 51 )
        AUC(0-tlast), 200 mg/m^2, Cycle 2 /Day 2 (n=11)
    55600 ( 51 )
        AUC(0-tlast), 250 mg/m^2, Cycle 1 /Day 2 (n=5)
    140000 ( 37 )
        AUC(0-tlast), 250 mg/m^2, Cycle 1 /Day 16 (n=3)
    98200 ( 139 )
        AUC(0-tlast), 250 mg/m^2, Cycle 2 /Day 2 (n=3)
    60400 ( 178 )
        AUC(0-tlast), 200 mg (flat), Cycle 1 /Day 2 (n=10)
    33100 ( 101 )
        AUC(0-tlast), 200 mg (flat), Cycle 1 /Day 16 (n=6)
    42600 ( 88 )
        AUC(0-tlast), 200 mg (flat), Cycle 2 /Day 2 (n=8)
    32400 ( 85 )
        AUC(0-tlast), 230 mg (flat), Cycle 1 /Day 2 (n=10)
    43000 ( 50 )
        AUC(0-tlast), 230 mg (flat), Cycle 1 /Day 16 (n=6)
    51900 ( 50 )
        AUC(0-tlast), 230 mg (flat), Cycle 2 /Day 2 (n=7)
    45900 ( 26 )
        AUC(0-inf), 70 mg/m^2, Cycle 1 /Day 2 (n=2)
    24900 ( 29 )
        AUC(0-inf), 70 mg/m^2, Cycle 1 /Day 16 (n=3)
    28600 ( 19 )
        AUC(0-inf), 70 mg/m^2, Cycle 2 /Day 2 (n=3)
    27100 ( 31 )
        AUC(0-inf), 105 mg/m^2, Cycle 1 /Day 2 (n=3)
    78600 ( 68 )
        AUC(0-inf), 105 mg/m^2, Cycle 1 /Day 16 (n=3)
    79800 ( 51 )
        AUC(0-inf), 105 mg/m^2, Cycle 2 /Day 2 (n=3)
    88800 ( 25 )
        AUC(0-inf), 150 mg/m^2, Cycle 1 /Day 2 (n=7)
    42800 ( 33 )
        AUC(0-inf), 150 mg/m^2, Cycle 1 /Day 16 (n=6)
    54600 ( 43 )
        AUC(0-inf), 150 mg/m^2, Cycle 2 /Day 2 (n=6)
    41000 ( 46 )
        AUC(0-inf), 200 mg/m^2, Cycle 1 /Day 2 (n=10)
    60300 ( 58 )
        AUC(0-inf), 200 mg/m^2, Cycle 1 /Day 16 (n=8)
    56800 ( 54 )
        AUC(0-inf), 200 mg/m^2, Cycle 2 /Day 2 (n=11)
    65400 ( 49 )
        AUC(0-inf), 250 mg/m^2, Cycle 1 /Day 2 (n=5)
    153000 ( 41 )
        AUC(0-inf), 250 mg/m^2, Cycle 1 /Day 16 (n=3)
    101000 ( 141 )
        AUC(0-inf), 250 mg/m^2, Cycle 2 /Day 2 (n=3)
    70500 ( 216 )
        AUC(0-inf), 200 mg (flat), Cycle 1 /Day 2 (n=10)
    35200 ( 117 )
        AUC(0-inf), 200 mg (flat), Cycle 1 /Day 16 (n=6)
    45700 ( 93 )
        AUC(0-inf), 200 mg (flat), Cycle 2 /Day 2 (n=8)
    34400 ( 93 )
        AUC(0-inf), 230 mg (flat), Cycle 1 /Day 2 (n=10)
    45200 ( 50 )
        AUC(0-inf), 230 mg (flat), Cycle 1 /Day 16 (n=6)
    57700 ( 58 )
        AUC(0-inf), 230 mg (flat), Cycle 2 /Day 2 (n=7)
    48000 ( 26 )
    No statistical analyses for this end point

    Secondary: Phase 2: Maximum Plasma Concentration (Cmax) of gemcitabine, dFdU, and LY2603618

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    End point title
    		 Phase 2: Maximum Plasma Concentration (Cmax) of gemcitabine, dFdU, and LY2603618 [7]
    End point description
    Plasma samples for PK analysis were collected following IV infusion of each study drug. However, the dose-normalized PK analysis of gemcitabine and dFdU were not reported because the gemcitabine and dFdU plasma concentration data generated for all participants with PK samples collected in this study were withdrawn (invalidated) as a result of the failure of the Incurred Sample Reanalysis (ISR) for both gemcitabine and dFdU. Therefore, only the LY2603618 plasma Cmax values are reported at the 230 mg LY2603618 dose level on Cycle 1 /Day 1, Cycle 1 /Day 16, and Cycle 2 /Day 2. The number of PK observations (n) used in the analysis is presented for each time point. Population analyzed was all phase 2 participants who received at least 1 dose of study drug and had sufficient LY2603618 plasma concentration data to enable determination of the LY2603618 Cmax.
    End point type
    Secondary
    End point timeframe
    Phase 2: LY2603618 - Predose and 0, 1, 3, and 24 hours after the end of infusion on Days 2 and 16 of Cycle 1. Gemcitabine - Predose and 0, 10, 60, and 120 minutes after the end of infusion on Days 1 and 15 of Cycle 1.
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are being reported for only phase 2 participants as per the protocol or Statistical Analysis Plan or both.
    End point values
    		 Phase 2: LY2603618 + Gemcitabine
    Number of subjects analysed
    62
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 /Day 2 (n=58)
    3170 ( 50 )
        Cycle 1 /Day 16 (n=48)
    3410 ( 50 )
        Cycle 2 /Day 2 (n=2)
    2390 ( 54 )
    No statistical analyses for this end point

    Secondary: Phase 2: Progression-free Survival (PFS)

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    End point title
    		 Phase 2: Progression-free Survival (PFS) [8]
    End point description
    Progression-free survival (PFS) time was defined as the time from the date of randomization to the first date of progressive disease (symptomatic or objective) or death due to any cause, whichever occurred first. For participants who were not known to have died or progressed as of the data-inclusion cutoff date, PFS time was censored at the date of the last objective progression-free disease assessment prior to the date of any subsequent systematic anticancer therapy. PFS was summarized using Kaplan-Meier estimates. Population analyzed was all phase 2 participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Phase 2: Baseline to measured progressive disease or date of death from any cause
    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: Statistics are being reported for only phase 2 participants as per the protocol or Statistical Analysis Plan or both.
    End point values
    		 Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Number of subjects analysed
    65
    34
    Units: months
        median (confidence interval 95%)
    3.5 (2.1 to 3.6)
    5.6 (2.6 to 7.6)
    No statistical analyses for this end point

    Secondary: Phase 2: Area Under the Plasma Concentration versus Time Curve (AUC) of gemcitabine, dFdU, and LY2603618

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    End point title
    		 Phase 2: Area Under the Plasma Concentration versus Time Curve (AUC) of gemcitabine, dFdU, and LY2603618 [9]
    End point description
    Plasma samples for PK analysis were collected following IV infusion of each study drug. However, the dose-normalized PK analysis of gemcitabine and dFdU were not reported because the gemcitabine and dFdU plasma concentration data generated for all participants with PK samples collected in this study were withdrawn (invalidated) as a result of the failure of the Incurred Sample Reanalysis (ISR) for both gemcitabine and dFdU. Therefore, only the LY2603618 plasma AUC(0-24), AUC(0-tlast), and AUC(0-inf) values are reported for the 230 mg LY2603618 dose on Cycle 1 /Day 1, Cycle 1 /Day 16, and Cycle 2 /Day 2. The number of PK observations (n) used in the analysis is presented for each time point. Population analyzed was all phase 2 participants who received at least 1 dose of study drug and had sufficient LY2603618 plasma concentration data to enable calculation of the LY2603618 AUC.
    End point type
    Secondary
    End point timeframe
    Phase 2: LY2603618 - Predose and 0, 1, 3, and 24 hours after the end of infusion on Days 2 and 16 of Cycle 1. Gemcitabine - Predose and 0, 10, 60, and 120 minutes after the end of infusion on Days 1 and 15 of Cycle 1.
    Notes
    [9] - 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: Statistics are being reported for only phase 2 participants as per the protocol or Statistical Analysis Plan or both.
    End point values
    		 Phase 2: LY2603618 + Gemcitabine
    Number of subjects analysed
    62
    Units: ng*h/mL
    geometric mean (geometric coefficient of variation)
        AUC(0-24), Cycle 1 /Day 2 (n=54)
    23200 ( 68 )
        AUC(0-24), Cycle 1 /Day 16 (n=42)
    23700 ( 60 )
        AUC(0-24), Cycle 2 /Day 2 (n=2)
    19800 ( 63 )
        AUC(0-tlast), Cycle 1 /Day 2 (n=58)
    22200 ( 73 )
        AUC(0-tlast), Cycle 1 /Day 16 (n=48)
    20800 ( 78 )
        AUC(0-tlast), Cycle 2 /Day 2 (n=2)
    20100 ( 64 )
        AUC(0-inf), Cycle 1 /Day 2 (n=54)
    29400 ( 84 )
        AUC(0-inf), Cycle 1 /Day 16 (n=42)
    29100 ( 74 )
        AUC(0-inf), Cycle 2 /Day 2 (n=2)
    23300 ( 69 )
    No statistical analyses for this end point

    Secondary: Phase 2: Overall Response Rate

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    End point title
    		 Phase 2: Overall Response Rate [10]
    End point description
    Overall response rate is the best response of complete response (CR) or partial response (PR) as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1) guidelines. CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. 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 not-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. Population analyzed was all phase 2 participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Phase 2: Baseline to measured progressive disease or date of death from any cause
    Notes
    [10] - 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: Statistics are being reported for only phase 2 participants as per the protocol or Statistical Analysis Plan or both.
    End point values
    		 Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Number of subjects analysed
    65
    34
    Units: percentage of participants
        number (confidence interval 95%)
    21.5 (12.3 to 33.5)
    8.8 (1.9 to 23.7)
    No statistical analyses for this end point

    Secondary: Phase 2: Clinical Benefit Rate

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    End point title
    		 Phase 2: Clinical Benefit Rate [11]
    End point description
    Clinical benefit rate is the best response CR, PR, or stable disease (SD) as classified by the investigators according to the RECIST v1.1 guidelines. CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. 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 not-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. Overall response 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. Population analyzed was all phase 2 participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Phase 2: Baseline to measured progressive disease or date of death from any cause
    Notes
    [11] - 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: Statistics are being reported for only phase 2 participants as per the protocol or Statistical Analysis Plan or both.
    End point values
    		 Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Number of subjects analysed
    65
    34
    Units: percentage of participants
        number (confidence interval 95%)
    55.4 (42.5 to 67.7)
    64.7 (46.5 to 80.3)
    No statistical analyses for this end point

    Secondary: Phase 2: Duration of Response

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    End point title
    		 Phase 2: Duration of Response [12]
    End point description
    Duration of response was defined as the time from the first observation of complete response (CR) or partial response (PR) to the first observation of progressive disease or death from any cause. For participants who were not known to have died as of the data-inclusion cut-off date and who do not have progressive disease, the duration was censored at the date of the last objective progression-free disease assessment prior to the date of any subsequent anticancer therapy (systemic, radiologic, or surgery). Participants were also censored at the last valid assessment prior to missing more than 1 consecutive scheduled assessment. Duration of response was summarized using Kaplan-Meier estimates. Population analyzed was all phase 2 participants who received at least 1 dose of study drug and had a confirmed response (CR or PR).
    End point type
    Secondary
    End point timeframe
    Phase 2. Baseline to measured progressive disease or date of death from any cause
    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: Statistics are being reported for only phase 2 participants as per the protocol or Statistical Analysis Plan or both.
    End point values
    		 Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Number of subjects analysed
    14
    3
    Units: months
        median (confidence interval 95%)
    3.5 (1.9 to 5.8)
    6 (3.7 to 6.8)
    No statistical analyses for this end point

    Secondary: Phase 2: Electrocardiogram QTc Prolongation

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    End point title
    		 Phase 2: Electrocardiogram QTc Prolongation [13]
    End point description
    The QT interval is a measure of the time between the start of the Q wave and the end of the T wave. Twelve-lead ECG data was used to calculate QTc based on Fridericia's formula (QTc=QT/RR^0.33, where RR is the interval between two R waves). For each participant, changes in QTc were calculated by subtracting the reading taken before LY2603618 administration from the reading taken after LY2603618 administration on Days 2 and 16 during Cycle 1. The number of participants in which the change in QTc was <=30 milliseconds (msec), >30-60 msec, or >60 msec is presented. Population analyzed was all phase 2 participants who received at least 1 dose of study drug and had evaluable ECG data.
    End point type
    Secondary
    End point timeframe
    Phase 2: Days 2 and 16 of Cycle 1
    Notes
    [13] - 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: Statistics are being reported for only phase 2 participants as per the protocol or Statistical Analysis Plan or both.
    End point values
    		 Phase 2: LY2603618 + Gemcitabine
    Number of subjects analysed
    60
    Units: participants
    number (not applicable)
        <=30 msec
    55
        >30-60 msec
    5
        >60 msec
    0
    No statistical analyses for this end point

    Secondary: Phase 1: Electrocardiogram QTc prolongation

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    End point title
    		 Phase 1: Electrocardiogram QTc prolongation [14]
    End point description
    The QT interval is a measure of the time between the start of the Q wave and the end of the T wave. Twelve-lead electrocardiogram (ECG) data was used to calculate the corrected QT (QTc) based on Fridericia's formula (QTc=QT/RR^0.33, where RR is the interval between two R waves). For each participant, changes in QTc were calculated by subtracting the reading taken before LY2603618 administration from the reading taken after LY2603618 administration on Days 2 and 16 during Cycle 1. The number of participants in which the change in QTc was <=30 milliseconds (msec), >30-60 msec, or >60 msec is presented by dose group and overall. Population analyzed was all phase 1 participants who received at least 1 dose of study drug and had evaluable ECG data.
    End point type
    Secondary
    End point timeframe
    Phase 1: Days 2 and 16 of Cycle 1
    Notes
    [14] - 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: Statistics are being reported for only phase 1 participants as per the protocol or Statistical Analysis Plan or both.
    End point values
    		 Phase 1: LY2603618 + Gemcitabine
    Number of subjects analysed
    49
    Units: participants
    number (not applicable)
        70 mg/m^2, <=30 msec (n=3)
    2
        70 mg/m^2, >30-60 msec (n=3)
    1
        70 mg/m^2, >60 msec (n=3)
    0
        105 mg/m^2, <=30 msec (n=3)
    2
        105 mg/m^2, >30-60 msec (n=3)
    0
        105 mg/m^2, >60 msec (n=3)
    0
        150 mg/m^2, <=30 msec (n=7)
    6
        150 mg/m^2, >30-60 msec (n=7)
    1
        150 mg/m^2, >60 msec (n=7)
    0
        200 mg/m^2, <=30 msec (n=11)
    11
        200 mg/m^2, >30-60 msec (n=11)
    0
        200 mg/m^2, >60 msec (n=11)
    0
        250 mg/m^2, <=30 msec (n=6)
    6
        250 mg/m^2, >30-60 msec (n=6)
    0
        250 mg/m^2, >60 msec (n=6)
    0
        200 mg (flat dose), <=30 msec (n=10)
    9
        200 mg (flat dose), >30-60 msec (n=10)
    1
        200 mg (flat dose), >60 msec (n=10)
    0
        230 mg (flat dose), <=30 msec (n=10)
    8
        230 mg (flat dose), >30-60 msec (n=10)
    2
        230 mg (flat dose), >60 msec (n=10)
    0
        Total, <=30 msec
    44
        Total, >30-60 msec
    5
        Total, >60 msec
    0
    No statistical analyses for this end point

    Other pre-specified: Number of Deaths During the Phase 1 Post-study Period

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    End point title
    		 Number of Deaths During the Phase 1 Post-study Period [15]
    End point description
    The number of participants who died during the post-study period of Phase 1 does not include the outcomes for the 4 participants who died while on treatment during Phase 2 as captured in the Participant Flow Table. A summary of serious and other non‐serious adverse events regardless of causality is located in the Reported Adverse Events module. Population analyzed was all phase 1 participants who received at least 1 dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    Phase 1: Time of last dose of study drug through the end of the follow-up period
    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: Statistics are being reported for only phase 1 participants as per the protocol or Statistical Analysis Plan or both.
    End point values
    		 Phase 1: LY2603618 + Gemcitabine
    Number of subjects analysed
    50
    Units: participants
    number (not applicable)
        Total deaths
    5
        Deaths within 30 days of last dose of study drug
    4
        Deaths during the follow-up period
    1
    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
    I2I-MC-JMMC
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Phase 1
    Reporting group description
    		 All participants in Phase 1 received LY2603618 in combination with gemcitabine. LY2603618: 70 to 250 mg/m^2 LY2603618 as a 1-hour continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Participants received LY2603618 as part of the dose escalation cohort of Phase 1 (dose of 70, 105, 150, 200, or 250 mg/m^2) or as part of the expansion cohort of Phase 1 (flat dose of 200 or 230 mg). The flat dose cohorts were conducted in parallel. Gemcitabine: 1000 mg/m^2 gemcitabine as a 30-minute continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Participants received gemcitabine 24 hours prior to LY2603618 administration.

    Reporting group title
    Phase 2: LY2603618 + Gemcitabine
    Reporting group description
    		 LY2603618: 230 mg flat dose LY2603618 as a 1-hour continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Gemcitabine: Participants were administered 1000 mg/m^2 gemcitabine as a 30-minute continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression. Participants received gemcitabine 24 hours prior to LY2603618 administration.

    Reporting group title
    Phase 2: Gemcitabine
    Reporting group description
    		 Gemcitabine: 1000 mg/m^2 gemcitabine as a 30-minute continuous IV infusion once per week for 3 weeks, followed by 1 week of rest. This 28-day cycle was repeated for a minimum of 2 cycles and/or until disease progression.

    Serious adverse events
    		 Phase 1 Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 50 (42.00%)
    27 / 65 (41.54%)
    18 / 34 (52.94%)
         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)
    malignant ascites
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    metastases to ovary
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed [1]
    0 / 24 (0.00%)
    0 / 23 (0.00%)
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    tumour pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    deep vein thrombosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hypotension
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    peripheral arterial occlusive disease
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    phlebitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    phlebitis superficial
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    0 / 34 (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
    venous thrombosis limb
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    device occlusion
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    fatigue
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pyrexia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 65 (4.62%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    thrombosis in device
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    drug hypersensitivity
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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 pulmonary oedema
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    acute respiratory failure
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    0 / 34 (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
    interstitial lung disease
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    0 / 34 (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
    pleural effusion
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pneumonitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 65 (3.08%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pulmonary embolism
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    respiratory failure
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    confusional state
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    Investigations
    c-reactive protein increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    international normalised ratio increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         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
    infusion related reaction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    0 / 34 (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
    Cardiac disorders
    angina pectoris
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         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 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 65 (3.08%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    bundle branch block left
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    left ventricular dysfunction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    myocardial infarction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 65 (3.08%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    cerebrovascular accident
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    syncope
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    disseminated intravascular coagulation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    haemolytic uraemic syndrome
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    haemorrhagic anaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    neutropenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    thrombocytopenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    thrombotic microangiopathy
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         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
    abdominal pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 65 (3.08%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ascites
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    colitis ischaemic
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    constipation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 65 (1.54%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    diarrhoea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    duodenal ulcer perforation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ileus
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ileus paralytic
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    intestinal ischaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    intestinal obstruction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    nausea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 50 (4.00%)
    1 / 65 (1.54%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pancreatic pseudocyst
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    pancreatitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    pancreatitis acute
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    small intestinal obstruction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    vomiting
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 65 (1.54%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    bile duct obstruction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    cholangitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 65 (4.62%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    cholecystitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    cholestasis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    jaundice
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    nephrotic syndrome
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    0 / 34 (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
    renal failure acute
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ureteric stenosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    abdominal sepsis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    bacteraemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 65 (1.54%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    bacterial sepsis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    bronchitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    cellulitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    clostridium difficile colitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    device related infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    escherichia bacteraemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    pneumonia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 65 (3.08%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    renal abscess
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    sepsis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    urinary tract infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    3 / 34 (8.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    dehydration
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    3 / 34 (8.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hyperkalaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    0 / 34 (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
    hyponatraemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    hypovolaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 65 (3.08%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female participants. The number of participants exposed has been adjusted accordingly.
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1 Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 50 (96.00%)
    64 / 65 (98.46%)
    34 / 34 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    tumour pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    3
    Vascular disorders
    deep vein thrombosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 65 (6.15%)
    3 / 34 (8.82%)
         occurrences all number
    1
    4
    3
    flushing
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    6 / 50 (12.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    8
    0
    0
    hypertension
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    3 / 65 (4.62%)
    3 / 34 (8.82%)
         occurrences all number
    1
    3
    3
    hypotension
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    5 / 50 (10.00%)
    3 / 65 (4.62%)
    5 / 34 (14.71%)
         occurrences all number
    5
    3
    5
    thrombophlebitis superficial
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    4 / 65 (6.15%)
    0 / 34 (0.00%)
         occurrences all number
    0
    4
    0
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    4 / 50 (8.00%)
    10 / 65 (15.38%)
    5 / 34 (14.71%)
         occurrences all number
    5
    19
    8
    chills
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    5 / 50 (10.00%)
    9 / 65 (13.85%)
    2 / 34 (5.88%)
         occurrences all number
    6
    15
    2
    fatigue
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    31 / 50 (62.00%)
    22 / 65 (33.85%)
    14 / 34 (41.18%)
         occurrences all number
    50
    28
    19
    influenza like illness
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    3 / 65 (4.62%)
    3 / 34 (8.82%)
         occurrences all number
    3
    8
    3
    infusion site pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    5 / 50 (10.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    10
    0
    4
    irritability
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    0
    non-cardiac chest pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 65 (1.54%)
    1 / 34 (2.94%)
         occurrences all number
    3
    1
    1
    oedema peripheral
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    8 / 50 (16.00%)
    19 / 65 (29.23%)
    12 / 34 (35.29%)
         occurrences all number
    9
    23
    16
    pyrexia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    15 / 50 (30.00%)
    19 / 65 (29.23%)
    11 / 34 (32.35%)
         occurrences all number
    33
    23
    14
    Immune system disorders
    drug hypersensitivity
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    5 / 50 (10.00%)
    2 / 65 (3.08%)
    0 / 34 (0.00%)
         occurrences all number
    5
    5
    0
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    10 / 50 (20.00%)
    7 / 65 (10.77%)
    5 / 34 (14.71%)
         occurrences all number
    12
    7
    6
    dysphonia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 65 (3.08%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    2
    dyspnoea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    8 / 50 (16.00%)
    12 / 65 (18.46%)
    2 / 34 (5.88%)
         occurrences all number
    11
    13
    2
    dyspnoea exertional
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 65 (3.08%)
    1 / 34 (2.94%)
         occurrences all number
    7
    2
    1
    epistaxis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    5 / 50 (10.00%)
    1 / 65 (1.54%)
    0 / 34 (0.00%)
         occurrences all number
    5
    2
    0
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 65 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    4
    0
    3
    confusional state
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    1 / 65 (1.54%)
    2 / 34 (5.88%)
         occurrences all number
    1
    1
    2
    depression
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    6 / 50 (12.00%)
    2 / 65 (3.08%)
    3 / 34 (8.82%)
         occurrences all number
    7
    2
    4
    insomnia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    7 / 50 (14.00%)
    4 / 65 (6.15%)
    6 / 34 (17.65%)
         occurrences all number
    9
    4
    8
    Investigations
    alanine aminotransferase increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    10 / 50 (20.00%)
    13 / 65 (20.00%)
    6 / 34 (17.65%)
         occurrences all number
    15
    18
    6
    aspartate aminotransferase increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    11 / 50 (22.00%)
    10 / 65 (15.38%)
    5 / 34 (14.71%)
         occurrences all number
    14
    15
    5
    blood alkaline phosphatase increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    5 / 65 (7.69%)
    3 / 34 (8.82%)
         occurrences all number
    0
    5
    3
    blood lactate dehydrogenase increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 65 (3.08%)
    3 / 34 (8.82%)
         occurrences all number
    1
    2
    3
    gamma-glutamyltransferase increased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    4 / 50 (8.00%)
    12 / 65 (18.46%)
    3 / 34 (8.82%)
         occurrences all number
    4
    12
    3
    haemoglobin decreased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 65 (3.08%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    3
    neutrophil count decreased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    3 / 65 (4.62%)
    2 / 34 (5.88%)
         occurrences all number
    0
    3
    6
    platelet count decreased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    7 / 65 (10.77%)
    1 / 34 (2.94%)
         occurrences all number
    0
    11
    5
    weight decreased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 50 (4.00%)
    7 / 65 (10.77%)
    3 / 34 (8.82%)
         occurrences all number
    3
    8
    3
    white blood cell count decreased
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 65 (3.08%)
    2 / 34 (5.88%)
         occurrences all number
    2
    4
    8
    Injury, poisoning and procedural complications
    infusion related reaction
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 65 (1.54%)
    0 / 34 (0.00%)
         occurrences all number
    3
    1
    0
    procedural pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    4
    0
    0
    Cardiac disorders
    sinus tachycardia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    3
    0
    1
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    5 / 50 (10.00%)
    5 / 65 (7.69%)
    4 / 34 (11.76%)
         occurrences all number
    5
    5
    4
    dysgeusia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    5 / 65 (7.69%)
    2 / 34 (5.88%)
         occurrences all number
    5
    5
    2
    headache
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    5 / 50 (10.00%)
    7 / 65 (10.77%)
    2 / 34 (5.88%)
         occurrences all number
    7
    10
    2
    peripheral sensory neuropathy
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    4 / 50 (8.00%)
    7 / 65 (10.77%)
    2 / 34 (5.88%)
         occurrences all number
    4
    8
    4
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    23 / 50 (46.00%)
    16 / 65 (24.62%)
    10 / 34 (29.41%)
         occurrences all number
    29
    21
    13
    leukocytosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 65 (1.54%)
    0 / 34 (0.00%)
         occurrences all number
    3
    1
    0
    leukopenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    4 / 50 (8.00%)
    8 / 65 (12.31%)
    6 / 34 (17.65%)
         occurrences all number
    5
    27
    10
    lymphopenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    5 / 50 (10.00%)
    4 / 65 (6.15%)
    4 / 34 (11.76%)
         occurrences all number
    6
    7
    4
    neutropenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    16 / 50 (32.00%)
    15 / 65 (23.08%)
    10 / 34 (29.41%)
         occurrences all number
    26
    49
    24
    thrombocytopenia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    23 / 50 (46.00%)
    23 / 65 (35.38%)
    15 / 34 (44.12%)
         occurrences all number
    46
    63
    39
    thrombocytosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 65 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    5
    Gastrointestinal disorders
    abdominal discomfort
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 65 (1.54%)
    0 / 34 (0.00%)
         occurrences all number
    3
    2
    0
    abdominal distension
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 65 (3.08%)
    2 / 34 (5.88%)
         occurrences all number
    4
    3
    2
    abdominal pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    12 / 50 (24.00%)
    14 / 65 (21.54%)
    5 / 34 (14.71%)
         occurrences all number
    12
    19
    7
    abdominal pain upper
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 50 (4.00%)
    5 / 65 (7.69%)
    1 / 34 (2.94%)
         occurrences all number
    2
    5
    1
    anorectal discomfort
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 65 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2
    constipation
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    17 / 50 (34.00%)
    21 / 65 (32.31%)
    9 / 34 (26.47%)
         occurrences all number
    22
    27
    10
    diarrhoea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    8 / 50 (16.00%)
    21 / 65 (32.31%)
    10 / 34 (29.41%)
         occurrences all number
    10
    36
    15
    dyspepsia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    4 / 65 (6.15%)
    1 / 34 (2.94%)
         occurrences all number
    3
    4
    1
    flatulence
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 65 (6.15%)
    0 / 34 (0.00%)
         occurrences all number
    1
    7
    0
    gastritis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 65 (1.54%)
    0 / 34 (0.00%)
         occurrences all number
    3
    1
    0
    haemorrhoids
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 65 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    2
    0
    2
    nausea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    20 / 50 (40.00%)
    27 / 65 (41.54%)
    15 / 34 (44.12%)
         occurrences all number
    25
    42
    21
    steatorrhoea
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 65 (1.54%)
    2 / 34 (5.88%)
         occurrences all number
    0
    1
    2
    stomatitis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    5 / 50 (10.00%)
    13 / 65 (20.00%)
    2 / 34 (5.88%)
         occurrences all number
    9
    14
    2
    vomiting
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    14 / 50 (28.00%)
    19 / 65 (29.23%)
    4 / 34 (11.76%)
         occurrences all number
    16
    35
    5
    Hepatobiliary disorders
    hyperbilirubinaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 50 (4.00%)
    2 / 65 (3.08%)
    4 / 34 (11.76%)
         occurrences all number
    2
    2
    4
    Skin and subcutaneous tissue disorders
    alopecia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    2 / 50 (4.00%)
    7 / 65 (10.77%)
    5 / 34 (14.71%)
         occurrences all number
    2
    8
    6
    decubitus ulcer
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 65 (6.15%)
    0 / 34 (0.00%)
         occurrences all number
    1
    4
    0
    dermatitis acneiform
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    4 / 50 (8.00%)
    2 / 65 (3.08%)
    0 / 34 (0.00%)
         occurrences all number
    5
    2
    0
    hyperhidrosis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 65 (1.54%)
    0 / 34 (0.00%)
         occurrences all number
    3
    1
    0
    pruritus
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 65 (6.15%)
    2 / 34 (5.88%)
         occurrences all number
    1
    6
    2
    Renal and urinary disorders
    pollakiuria
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    0
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 65 (1.54%)
    0 / 34 (0.00%)
         occurrences all number
    3
    1
    0
    back pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    6 / 50 (12.00%)
    9 / 65 (13.85%)
    4 / 34 (11.76%)
         occurrences all number
    6
    10
    4
    muscular weakness
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    7 / 50 (14.00%)
    2 / 65 (3.08%)
    2 / 34 (5.88%)
         occurrences all number
    9
    2
    2
    musculoskeletal chest pain
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 65 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    3
    0
    2
    pain in extremity
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    5 / 50 (10.00%)
    8 / 65 (12.31%)
    1 / 34 (2.94%)
         occurrences all number
    7
    9
    1
    Infections and infestations
    oral candidiasis
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 65 (1.54%)
    1 / 34 (2.94%)
         occurrences all number
    4
    2
    1
    upper respiratory tract infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    4
    0
    0
    urinary tract infection
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    2 / 65 (3.08%)
    3 / 34 (8.82%)
         occurrences all number
    3
    2
    3
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    16 / 50 (32.00%)
    21 / 65 (32.31%)
    5 / 34 (14.71%)
         occurrences all number
    19
    22
    6
    dehydration
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    1 / 65 (1.54%)
    3 / 34 (8.82%)
         occurrences all number
    4
    1
    3
    hyperglycaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    12 / 65 (18.46%)
    4 / 34 (11.76%)
         occurrences all number
    8
    13
    6
    hyperkalaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    0 / 50 (0.00%)
    2 / 65 (3.08%)
    3 / 34 (8.82%)
         occurrences all number
    0
    2
    4
    hypoalbuminaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    4 / 65 (6.15%)
    3 / 34 (8.82%)
         occurrences all number
    2
    4
    3
    hypocalcaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 65 (3.08%)
    6 / 34 (17.65%)
         occurrences all number
    1
    4
    6
    hypokalaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    4 / 50 (8.00%)
    1 / 65 (1.54%)
    5 / 34 (14.71%)
         occurrences all number
    4
    1
    6
    hyponatraemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    6 / 65 (9.23%)
    5 / 34 (14.71%)
         occurrences all number
    4
    7
    5
    hypovolaemia
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    4 / 50 (8.00%)
    0 / 65 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    8
    0
    0
    vitamin d deficiency
    alternative dictionary used: MedDRA 15.1
         subjects affected / exposed
    3 / 50 (6.00%)
    0 / 65 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    3
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Sep 2009
    Amendment (a) clarified dose omissions/reductions during a cycle, declaration of a DLT, and description of the MTD that will be carried into Phase 2. The ECG collection was also clarified.
    30 Jun 2010
    Amendment (b) added 2 additional cohorts of patients (n=20) prior to selecting the recommended Phase 2 dose.

    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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