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A Study for Participants With Pancreatic Cancer

Sponsor
Eli Lilly and Company (Industry)
Overall Status
Completed
CT.gov ID
NCT00839332
Collaborator
(none)
157
Enrollment
30
Locations
2
Arms
58
Duration (Months)
5.2
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Detailed Description

Phase 1 included a dose escalation of LY2603618 doses from 70 milligrams/meter squared (mg/m2) to 250 mg/m2 divided into 5 cohorts. Each participant was assigned to a single cohort with no intra-participant dose escalation. Phase 1 also included an expansion cohort where participants received a flat dose of 200 or 230 mg LY2603618. Participants received gemcitabine on Days 1, 8, and 15, followed by LY2603618 on Days 2, 9, and 16 of each 28-day cycle. The purpose of the Phase 1 portion was to determine the maximum tolerated LY2603618 dose to be carried into the Phase 2 portion of the study.

Study Design

Study Type:
Interventional
Actual Enrollment :
157 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1/Randomized Phase 2 Study to Evaluate LY2603618 in Combination With Gemcitabine in Patients With Pancreatic Cancer
Study Start Date :
Feb 1, 2009
Actual Primary Completion Date :
Feb 1, 2013
Actual Study Completion Date :
Dec 1, 2013

Arms and Interventions

Arm Intervention/Treatment
Experimental: LY2603618 + Gemcitabine

Participants participated in Phase 1 or 2. LY2603618 (Phase 1): 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 (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). LY2603618 (Phase 2): 230 mg 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 DP. Gemcitabine (Phase 1 and 2): 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.

Drug: LY2603618

Drug: Gemcitabine
Other Names:
  • Gemzar
  • LY188011

    		•
    Active Comparator: Gemcitabine

    Participants participated in Phase 2 only. Gemcitabine (Phase 2): 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.

    Drug: Gemcitabine
    Other Names:
  • Gemzar
  • LY188011

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Phase 1: Determine the Recommended Phase 2 Dose for LY2603618 When Administered After Gemcitabine [Baseline through 18 months]

      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]).

    2. Phase 2: Overall Survival (OS) [Phase 2: Baseline to date of death]

      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.

    Secondary Outcome Measures

    1. Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 [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.]

      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.

    2. Phase 2: Maximum Plasma Concentration (Cmax) of Gemcitabine, dFdU, and LY2603618 [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.]

      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.

    3. Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 [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.]

      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 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 LY2603618 plasma AUC from time zero to 24 hours (AUC[0-24]), AUC from time zero to the last time point with a measurable concentration (AUC[0-tlast]), and AUC from time zero to infinity (AUC[0-inf]) values are reported for each 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 dose level and time point.

    4. Phase 2: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 [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.]

      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.

    5. Phase 2: Progression-free Survival (PFS) [Phase 2: Baseline to measured progressive disease or date of death from any cause]

      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.

    6. Phase 2: Overall Response Rate [Phase 2: Baseline to measured progressive disease or date of death from any cause]

      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.

    7. Phase 2: Clinical Benefit Rate [Phase 2: Baseline to measured progressive disease or date of death from any cause]

      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.

    8. Phase 2: Duration of Response [Phase 2. Baseline to measured progressive disease or date of death from any cause]

      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.

    9. Phase 1: Electrocardiogram QTc Prolongation [Phase 1: Days 2 and 16 of Cycle 1]

      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.

    10. Phase 2: Electrocardiogram QTc Prolongation [Phase 2: Days 2 and 16 of Cycle 1]

      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.

    Other Outcome Measures

    1. Number of Deaths During the Phase 1 Post-study Period [Phase 1: Time of last dose of study drug through the end of the follow-up period]

      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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 85 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • Diagnosed with cancer that is metastatic and/or advanced during Phase 1

    • Diagnosed with pancreatic cancer that is metastatic and not amenable to surgery

    • Must be at least 18 years of age

    • Adequate hematological, liver, and renal functions

    • Eastern Cooperative Oncology Group (ECOG) status of 0 to 2

    Exclusion Criteria:

    • Known hypersensitivity to gemcitabine

    • Pregnant or lactating females or refusal to use medically approved contraceptive precautions

    • Had prior treatment with radiotherapy involving more than 25% of marrow producing area

    • Have received treatment in the last 30 days with a drug which has not received regulatory approval for any indication at the time of study entry

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Jacksonville Florida United States 32224
    2 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Athens Georgia United States 30607
    3 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Macon Georgia United States 31201
    4 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Post Falls Idaho United States 83854
    5 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Sioux City Iowa United States 51101
    6 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Ann Arbor Michigan United States 48106
    7 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Rochester Minnesota United States 55905
    8 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Fargo North Dakota United States 58122
    9 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Danville Pennsylvania United States 17822
    10 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Sioux Falls South Dakota United States 57104
    11 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Memphis Tennessee United States 38119
    12 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. San Antonio Texas United States 78217
    13 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. The Woodlands Texas United States 77380
    14 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Tyler Texas United States 75702
    15 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Hampton Virginia United States 23666
    16 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Green Bay Wisconsin United States 54307
    17 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Berlin Germany 13353
    18 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Frankfurt Germany 60596
    19 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Freiburg Germany D-79106
    20 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Hamburg Germany 20246
    21 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Heilbronn Germany 74078
    22 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Nürnberg Germany 90419
    23 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Ancona Italy 60126
    24 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Firenze Italy 50139
    25 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Mendola Italy 47014
    26 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Amsterdam Netherlands 1105 AZ
    27 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Bucharest Romania
    28 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Cluj-Napoca Romania 400015
    29 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Hospitalet De Llobregat Spain 08908
    30 For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician. Madrid Spain 28050

    Sponsors and Collaborators

    • Eli Lilly and Company

    Investigators

    • Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon-Fri 9AM-5PM Eastern time (UTC/GMT-5 hours, EST), Eli Lilly and Company

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT00839332
    Other Study ID Numbers:
    • 12096
    • I2I-MC-JMMC
    First Posted:
    Feb 9, 2009
    Last Update Posted:
    Apr 17, 2018
    Last Verified:
    Mar 1, 2018
    Keywords provided by Eli Lilly and Company
    Pancreas
    metastatic cancer
    advanced cancer
    Pancreatic cancer
    Additional relevant MeSH terms:
    Pancreatic Neoplasms
    Gemcitabine

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Phase 1: LY2603618 + Gemcitabine Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Arm/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. 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. 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.
    Period Title: Phase 1
    STARTED 50 0 0
    Received at Least 1 Dose of Study Drug 50 0 0
    COMPLETED 0 0 0
    NOT COMPLETED 50 0 0
    Period Title: Phase 1
    STARTED 0 68 39
    Received at Least 1 Dose of Study Drug 0 65 34
    COMPLETED 0 0 0
    NOT COMPLETED 0 68 39

    Baseline Characteristics

    Arm/Group Title Phase 1: LY2603618 + Gemcitabine Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine Total
    Arm/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. 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. 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. Total of all reporting groups
    Overall Participants 50 65 34 149
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    59.0
    (12.2)
    64.3
    (8.3)
    64.4
    (10.1)
    62.54
    (11.8)
    Sex: Female, Male (Count of Participants)
    Female
    24
    48%
    23
    35.4%
    14
    41.2%
    61
    40.9%
    Male
    26
    52%
    42
    64.6%
    20
    58.8%
    88
    59.1%
    Race/Ethnicity, Customized (Count of Participants)
    White
    46
    92%
    62
    95.4%
    32
    94.1%
    140
    94%
    Black or African American
    1
    2%
    2
    3.1%
    2
    5.9%
    5
    3.4%
    American Indian or Alaska Native
    0
    0%
    1
    1.5%
    0
    0%
    1
    0.7%
    Asian
    3
    6%
    0
    0%
    0
    0%
    3
    2%
    Region of Enrollment (Count of Participants)
    United States
    32
    64%
    27
    41.5%
    14
    41.2%
    73
    49%
    Spain
    18
    36%
    12
    18.5%
    5
    14.7%
    35
    23.5%
    Romania
    0
    0%
    2
    3.1%
    1
    2.9%
    3
    2%
    Germany
    0
    0%
    17
    26.2%
    9
    26.5%
    26
    17.4%
    Netherlands
    0
    0%
    3
    4.6%
    2
    5.9%
    5
    3.4%
    Italy
    0
    0%
    3
    4.6%
    2
    5.9%
    5
    3.4%
    Poland
    0
    0%
    1
    1.5%
    1
    2.9%
    2
    1.3%
    Initial Pathological Diagnosis (Count of Participants)
    Adenocarcinoma, Pancreas
    10
    20%
    65
    100%
    34
    100%
    109
    73.2%
    Adenocarcinoma, Colon
    7
    14%
    0
    0%
    0
    0%
    7
    4.7%
    Carcinoma, Breast
    4
    8%
    0
    0%
    0
    0%
    4
    2.7%
    Carcinoma, Non-Small Cell, Lung NOS
    3
    6%
    0
    0%
    0
    0%
    3
    2%
    Adenocarcinoma, Cervix
    2
    4%
    0
    0%
    0
    0%
    2
    1.3%
    Adenocarcinoma, Rectum
    2
    4%
    0
    0%
    0
    0%
    2
    1.3%
    Carcinoma, Endometrium
    2
    4%
    0
    0%
    0
    0%
    2
    1.3%
    Carcinoma, Infiltrating Ductal, Breast
    2
    4%
    0
    0%
    0
    0%
    2
    1.3%
    Carcinoma, Renal Cell
    2
    4%
    0
    0%
    0
    0%
    2
    1.3%
    Sarcoma, Leiomyosarcoma, Abdomen (Non-Gist)
    2
    4%
    0
    0%
    0
    0%
    2
    1.3%
    Squamous Cell Carcinoma, Head and Neck
    2
    4%
    0
    0%
    0
    0%
    2
    1.3%
    Ampulla of Pancreas
    1
    2%
    0
    0%
    0
    0%
    1
    0.7%
    Carcinoma, Head and Neck
    1
    2%
    0
    0%
    0
    0%
    1
    0.7%
    Carcinoma, Ovarian
    1
    2%
    0
    0%
    0
    0%
    1
    0.7%
    Carcinoma, Peritoneal
    1
    2%
    0
    0%
    0
    0%
    1
    0.7%
    Carcinoma, Small Cell, Lung
    1
    2%
    0
    0%
    0
    0%
    1
    0.7%
    Carcinoma, Transitional Cell, Urothelium
    1
    2%
    0
    0%
    0
    0%
    1
    0.7%
    Ewing's Sarcoma
    1
    2%
    0
    0%
    0
    0%
    1
    0.7%
    Lymphoma, Non-Hodgkin's Lymphoma
    1
    2%
    0
    0%
    0
    0%
    1
    0.7%
    Mesothelioma, Pleural, Malignant
    1
    2%
    0
    0%
    0
    0%
    1
    0.7%
    Ovarian Adenocarcinoma
    1
    2%
    0
    0%
    0
    0%
    1
    0.7%
    Squamous Cell Carcinoma, Cervix
    1
    2%
    0
    0%
    0
    0%
    1
    0.7%
    Tumor
    1
    2%
    0
    0%
    0
    0%
    1
    0.7%
    Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
    ECOG Status 0
    19
    38%
    28
    43.1%
    14
    41.2%
    61
    40.9%
    ECOG Status 1
    31
    62%
    31
    47.7%
    17
    50%
    79
    53%
    ECOG Status 2
    0
    0%
    6
    9.2%
    3
    8.8%
    9
    6%

    Outcome Measures

    1. Primary Outcome
    Title Phase 1: Determine the Recommended Phase 2 Dose for LY2603618 When Administered After Gemcitabine
    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]).
    Time Frame Baseline through 18 months

    Outcome Measure Data

    Analysis Population Description
    Phase 1 participants who received at least 1 dose of study drug.
    Arm/Group Title Phase 1: LY2603618 + Gemcitabine
    Arm/Group Description All participants in Phase 1 received LY2603618 in combination with gemcitabine. LY2603618: 70-250 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.
    Measure Participants 50
    Number [milligrams (mg)]
    230
    2. Primary Outcome
    Title Phase 2: Overall Survival (OS)
    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.
    Time Frame Phase 2: Baseline to date of death

    Outcome Measure Data

    Analysis Population Description
    Phase 2 participants who were randomized.
    Arm/Group Title Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Arm/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. 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.
    Measure Participants 65 34
    Median (95% Confidence Interval) [months]
    7.8
    8.3
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Phase 1: LY2603618 + Gemcitabine, Phase 2: Gemcitabine
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value
    Comments
    Method
    Comments
    Method of Estimation Estimation Parameter Bayesian Posterior Probability
    Estimated Value 0.333
    Confidence Interval (2-Sided) %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments 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.
    3. Secondary Outcome
    Title Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618
    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.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    Phase 1 participants who received at least 1 dose of study drug (LY2603618) and had sufficient LY2603618 plasma concentration data to enable determination of the LY2603618 Cmax.
    Arm/Group Title Phase 1: LY2603618 + Gemcitabine
    Arm/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.
    Measure Participants 50
    70 mg/m^2, Cycle 1 /Day 2
    3530
    (23)
    70 mg/m^2, Cycle 1 /Day 16
    3360
    (26)
    70 mg/m^2, Cycle 2 /Day 2
    3100
    (12)
    105 mg/m^2, Cycle 1 /Day 2
    4890
    (25)
    105 mg/m^2, Cycle 1 /Day 16
    5170
    (38)
    105 mg/m^2, Cycle 2 /Day 2
    5360
    (23)
    150 mg/m^2, Cycle 1 /Day 2
    4280
    (29)
    150 mg/m^2, Cycle 1 /Day 16
    5040
    (38)
    150 mg/m^2, Cycle 2 /Day 2
    4370
    (38)
    200 mg/m^2, Cycle 1 /Day 2
    4870
    (63)
    200 mg/m^2, Cycle 1 /Day 16
    5360
    (40)
    200 mg/m^2, Cycle 2 /Day 2
    5290
    (40)
    250 mg/m^2, Cycle 1 /Day 2
    7990
    (25)
    250 mg/m^2, Cycle 1 /Day 16
    7990
    (6)
    250 mg/m^2, Cycle 2 /Day 2
    5290
    (35)
    200 mg (flat dose), Cycle 1 /Day 2
    3440
    (65)
    200 mg (flat dose), Cycle 1 /Day 16
    3470
    (61)
    200 mg (flat dose), Cycle 2 /Day 2
    3640
    (45)
    230 mg (flat dose), Cycle 1 /Day 2
    4820
    (72)
    230 mg (flat dose), Cycle 1 /Day 16
    4980
    (35)
    230 mg (flat dose), Cycle 2 /Day 2
    3830
    (26)
    4. Secondary Outcome
    Title Phase 2: Maximum Plasma Concentration (Cmax) of Gemcitabine, dFdU, and LY2603618
    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.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    Phase 2 participants who received at least 1 dose of study drug (LY2603618) and had sufficient LY2603618 plasma concentration data to enable determination of the LY2603618 Cmax.
    Arm/Group Title Phase 2: LY2603618 + Gemcitabine
    Arm/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.
    Measure Participants 62
    Cycle 1 /Day 2
    3170
    (50)
    Cycle 1 /Day 16
    3410
    (50)
    Cycle 2 /Day 2
    2390
    (54)
    5. Secondary Outcome
    Title Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618
    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 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 LY2603618 plasma AUC from time zero to 24 hours (AUC[0-24]), AUC from time zero to the last time point with a measurable concentration (AUC[0-tlast]), and AUC from time zero to infinity (AUC[0-inf]) values are reported for each 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 dose level and time point.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    Phase 1 participants who received at least 1 dose of study drug (LY2603618) and had sufficient LY2603618 plasma concentration data to enable calculation of the LY2603618 AUC.
    Arm/Group Title Phase 1: LY2603618 + Gemcitabine
    Arm/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.
    Measure Participants 50
    AUC(0-24), 70 mg/m^2, Cycle 1 /Day 2
    21300
    (24)
    AUC(0-24), 70 mg/m^2, Cycle 1 /Day 16
    21200
    (27)
    AUC(0-24), 70 mg/m^2, Cycle 2 /Day 2
    19900
    (24)
    AUC(0-24), 105 mg/m^2, Cycle 1 /Day 2
    40500
    (23)
    AUC(0-24), 105 mg/m^2, Cycle 1 /Day 16
    50100
    (32)
    AUC(0-24), 105 mg/m^2, Cycle 2 /Day 2
    49800
    (4)
    AUC(0-24), 150 mg/m^2, Cycle 1 /Day 2
    32200
    (27)
    AUC(0-24), 150 mg/m^2, Cycle 1 /Day 16
    40000
    (29)
    AUC(0-24), 150 mg/m^2, Cycle 2 /Day 2
    31000
    (42)
    AUC(0-24), 200 mg/m^2, Cycle 1 /Day 2
    40200
    (42)
    AUC(0-24), 200 mg/m^2, Cycle 1 /Day 16
    39800
    (36)
    AUC(0-24), 200 mg/m^2, Cycle 2 /Day 2
    44300
    (39)
    AUC(0-24), 250 mg/m^2, Cycle 1 /Day 2
    88800
    (27)
    AUC(0-24), 250 mg/m^2, Cycle 1 /Day 16
    61000
    (63)
    AUC(0-24), 250 mg/m^2, Cycle 2 /Day 2
    40000
    (112)
    AUC(0-24), 200 mg (flat), Cycle 1 /Day 2
    22900
    (77)
    AUC(0-24), 200 mg (flat), Cycle 1 /Day 16
    28700
    (63)
    AUC(0-24), 200 mg (flat), Cycle 2 /Day 2
    23800
    (62)
    AUC(0-24), 230 mg (flat), Cycle 1 /Day 2
    32400
    (38)
    AUC(0-24), 230 mg (flat), Cycle 1 /Day 16
    32300
    (22)
    AUC(0-24), 230 mg (flat), Cycle 2 /Day 2
    32500
    (24)
    AUC(0-tlast), 70 mg/m^2, Cycle 1 /Day 2
    24600
    (28)
    AUC(0-tlast), 70 mg/m^2, Cycle 1 /Day 16
    27500
    (21)
    AUC(0-tlast), 70 mg/m^2, Cycle 2 /Day 2
    25800
    (29)
    AUC(0-tlast), 105 mg/m^2, Cycle 1 /Day 2
    65800
    (53)
    AUC(0-tlast), 105 mg/m^2, Cycle 1 /Day 16
    75500
    (46)
    AUC(0-tlast), 105 mg/m^2, Cycle 2 /Day 2
    79600
    (19)
    AUC(0-tlast), 150 mg/m^2, Cycle 1 /Day 2
    41600
    (31)
    AUC(0-tlast), 150 mg/m^2, Cycle 1 /Day 16
    52000
    (38)
    AUC(0-tlast), 150 mg/m^2, Cycle 2 /Day 2
    39800
    (45)
    AUC(0-tlast), 200 mg/m^2, Cycle 1 /Day 2
    44300
    (85)
    AUC(0-tlast), 200 mg/m^2, Cycle 1 /Day 16
    55300
    (51)
    AUC(0-tlast), 200 mg/m^2, Cycle 2 /Day 2
    55600
    (51)
    AUC(0-tlast), 250 mg/m^2, Cycle 1 /Day 2
    140000
    (37)
    AUC(0-tlast), 250 mg/m^2, Cycle 1 /Day 16
    98200
    (139)
    AUC(0-tlast), 250 mg/m^2, Cycle 2 /Day 2
    60400
    (178)
    AUC(0-tlast), 200 mg (flat), Cycle 1 /Day 2
    33100
    (101)
    AUC(0-tlast), 200 mg (flat), Cycle 1 /Day 16
    42600
    (88)
    AUC(0-tlast), 200 mg (flat), Cycle 2 /Day 2
    32400
    (85)
    AUC(0-tlast), 230 mg (flat), Cycle 1 /Day 2
    43000
    (50)
    AUC(0-tlast), 230 mg (flat), Cycle 1 /Day 16
    51900
    (50)
    AUC(0-tlast), 230 mg (flat), Cycle 2 /Day 2
    45900
    (26)
    AUC(0-inf), 70 mg/m^2, Cycle 1 /Day 2
    24900
    (29)
    AUC(0-inf), 70 mg/m^2, Cycle 1 /Day 16
    28600
    (19)
    AUC(0-inf), 70 mg/m^2, Cycle 2 /Day 2
    27100
    (31)
    AUC(0-inf), 105 mg/m^2, Cycle 1 /Day 2
    78600
    (68)
    AUC(0-inf), 105 mg/m^2, Cycle 1 /Day 16
    79800
    (51)
    AUC(0-inf), 105 mg/m^2, Cycle 2 /Day 2
    88800
    (25)
    AUC(0-inf), 150 mg/m^2, Cycle 1 /Day 2
    42800
    (33)
    AUC(0-inf), 150 mg/m^2, Cycle 1 /Day 16
    54600
    (43)
    AUC(0-inf), 150 mg/m^2, Cycle 2 /Day 2
    41000
    (46)
    AUC(0-inf), 200 mg/m^2, Cycle 1 /Day 2
    60300
    (58)
    AUC(0-inf), 200 mg/m^2, Cycle 1 /Day 16
    56800
    (54)
    AUC(0-inf), 200 mg/m^2, Cycle 2 /Day 2
    65400
    (49)
    AUC(0-inf), 250 mg/m^2, Cycle 1 /Day 2
    153000
    (41)
    AUC(0-inf), 250 mg/m^2, Cycle 1 /Day 16
    101000
    (141)
    AUC(0-inf), 250 mg/m^2, Cycle 2 /Day 2
    70500
    (216)
    AUC(0-inf), 200 mg (flat), Cycle 1 /Day 2
    35200
    (117)
    AUC(0-inf), 200 mg (flat), Cycle 1 /Day 16
    45700
    (93)
    AUC(0-inf), 200 mg (flat), Cycle 2 /Day 2
    34400
    (93)
    AUC(0-inf), 230 mg (flat), Cycle 1 /Day 2
    45200
    (50)
    AUC(0-inf), 230 mg (flat), Cycle 1 /Day 16
    57700
    (58)
    AUC(0-inf), 230 mg (flat), Cycle 2 /Day 2
    48000
    (26)
    6. Secondary Outcome
    Title Phase 2: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618
    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.
    Time Frame 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.

    Outcome Measure Data

    Analysis Population Description
    Phase 2 participants who received at least 1 dose of study drug (LY2603618) and had sufficient LY2603618 plasma concentration data to enable calculation of the LY2603618 AUC.
    Arm/Group Title Phase 2: LY2603618 + Gemcitabine
    Arm/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.
    Measure Participants 62
    AUC(0-24), Cycle 1 /Day 2
    23200
    (68)
    AUC(0-24), Cycle 1 /Day 16
    23700
    (60)
    AUC(0-24), Cycle 2 /Day 2
    19800
    (63)
    AUC(0-tlast), Cycle 1 /Day 2
    22200
    (73)
    AUC(0-tlast), Cycle 1 /Day 16
    20800
    (78)
    AUC(0-tlast), Cycle 2 /Day 2
    20100
    (64)
    AUC(0-inf), Cycle 1 /Day 2
    29400
    (84)
    AUC(0-inf), Cycle 1 /Day 16
    29100
    (74)
    AUC(0-inf), Cycle 2 /Day 2
    23300
    (69)
    7. Secondary Outcome
    Title Phase 2: Progression-free Survival (PFS)
    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.
    Time Frame Phase 2: Baseline to measured progressive disease or date of death from any cause

    Outcome Measure Data

    Analysis Population Description
    Phase 2 participants who were randomized.
    Arm/Group Title Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Arm/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. 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.
    Measure Participants 65 34
    Median (95% Confidence Interval) [months]
    3.5
    5.6
    8. Secondary Outcome
    Title Phase 2: Overall Response Rate
    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.
    Time Frame Phase 2: Baseline to measured progressive disease or date of death from any cause

    Outcome Measure Data

    Analysis Population Description
    Phase 2 participants who were randomized.
    Arm/Group Title Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Arm/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. 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.
    Measure Participants 65 34
    Number (95% Confidence Interval) [percentage of participants]
    21.5
    43%
    8.8
    13.5%
    9. Secondary Outcome
    Title Phase 2: Clinical Benefit Rate
    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.
    Time Frame Phase 2: Baseline to measured progressive disease or date of death from any cause

    Outcome Measure Data

    Analysis Population Description
    Phase 2 participants who were randomized.
    Arm/Group Title Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Arm/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. 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.
    Measure Participants 65 34
    Number (95% Confidence Interval) [percentage of participants]
    55.4
    110.8%
    64.7
    99.5%
    10. Other Pre-specified Outcome
    Title Number of Deaths During the Phase 1 Post-study Period
    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.
    Time Frame Phase 1: Time of last dose of study drug through the end of the follow-up period

    Outcome Measure Data

    Analysis Population Description
    Participants enrolled in Phase 1.
    Arm/Group Title Phase 1: LY2603618 + Gemcitabine
    Arm/Group Description All participants in Phase 1 received LY2603618 in combination with gemcitabine. LY2603618: 70-250 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.
    Measure Participants 50
    Total deaths
    5
    10%
    Deaths within 30 days of last dose of study drug
    4
    8%
    Deaths during the follow-up period
    1
    2%
    11. Secondary Outcome
    Title Phase 2: Duration of Response
    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.
    Time Frame Phase 2. Baseline to measured progressive disease or date of death from any cause

    Outcome Measure Data

    Analysis Population Description
    Phase 2 participants who received at least 1 dose of study drug and had a confirmed response (CR or PR).
    Arm/Group Title Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Arm/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. 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.
    Measure Participants 14 3
    Median (95% Confidence Interval) [months]
    3.5
    6.0
    12. Secondary Outcome
    Title Phase 1: Electrocardiogram QTc Prolongation
    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.
    Time Frame Phase 1: Days 2 and 16 of Cycle 1

    Outcome Measure Data

    Analysis Population Description
    Phase 1 participants who received at least 1 dose of LY2603618 and had evaluable ECG data.
    Arm/Group Title Phase 1: LY2603618 + Gemcitabine
    Arm/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.
    Measure Participants 49
    70 mg/m^2, <=30 msec
    2
    4%
    70 mg/m^2, >30-60 msec
    1
    2%
    70 mg/m^2, >60 msec
    0
    0%
    105 mg/m^2, <=30 msec
    2
    4%
    105 mg/m^2, >30-60 msec
    0
    0%
    105 mg/m^2, >60 msec
    0
    0%
    150 mg/m^2, <=30 msec
    6
    12%
    150 mg/m^2, >30-60 msec
    1
    2%
    150 mg/m^2, >60 msec
    0
    0%
    200 mg/m^2, <=30 msec
    11
    22%
    200 mg/m^2, >30-60 msec
    0
    0%
    200 mg/m^2, >60 msec
    0
    0%
    250 mg/m^2, <=30 msec
    6
    12%
    250 mg/m^2, >30-60 msec
    0
    0%
    250 mg/m^2, >60 msec
    0
    0%
    200 mg (flat dose), <=30 msec
    9
    18%
    200 mg (flat dose), >30-60 msec
    1
    2%
    200 mg (flat dose), >60 msec
    0
    0%
    230 mg (flat dose), <=30 msec
    8
    16%
    230 mg (flat dose), >30-60 msec
    2
    4%
    230 mg (flat dose), >60 msec
    0
    0%
    Total, <=30 msec
    44
    88%
    Total, >30-60 msec
    5
    10%
    Total, >60 msec
    0
    0%
    13. Secondary Outcome
    Title Phase 2: Electrocardiogram QTc Prolongation
    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.
    Time Frame Phase 2: Days 2 and 16 of Cycle 1

    Outcome Measure Data

    Analysis Population Description
    Phase 2 participants who received at least 1 dose of LY2603618 and had evaluable ECG data.
    Arm/Group Title Phase 2: LY2603618 + Gemcitabine
    Arm/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.
    Measure Participants 60
    <=30 msec
    55
    110%
    >30-60 msec
    5
    10%
    >60 msec
    0
    0%

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Phase 1: LY2603618 + Gemcitabine Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Arm/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. 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. 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.
    All Cause Mortality
    Phase 1: LY2603618 + Gemcitabine Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Phase 1: LY2603618 + Gemcitabine Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 21/50 (42%) 27/65 (41.5%) 18/34 (52.9%)
    Blood and lymphatic system disorders
    Anaemia 0/50 (0%) 0 1/65 (1.5%) 1 1/34 (2.9%) 1
    Disseminated intravascular coagulation 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Haemolytic uraemic syndrome 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Haemorrhagic anaemia 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Neutropenia 2/50 (4%) 2 0/65 (0%) 0 0/34 (0%) 0
    Thrombocytopenia 3/50 (6%) 3 0/65 (0%) 0 0/34 (0%) 0
    Thrombotic microangiopathy 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Cardiac disorders
    Angina pectoris 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Atrial fibrillation 0/50 (0%) 0 2/65 (3.1%) 2 0/34 (0%) 0
    Bundle branch block left 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Left ventricular dysfunction 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Myocardial infarction 0/50 (0%) 0 2/65 (3.1%) 2 0/34 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 0/50 (0%) 0 2/65 (3.1%) 2 2/34 (5.9%) 2
    Ascites 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Colitis ischaemic 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Constipation 1/50 (2%) 1 1/65 (1.5%) 1 0/34 (0%) 0
    Diarrhoea 1/50 (2%) 1 0/65 (0%) 0 1/34 (2.9%) 1
    Duodenal ulcer perforation 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Ileus 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Ileus paralytic 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Intestinal ischaemia 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Intestinal obstruction 2/50 (4%) 2 0/65 (0%) 0 0/34 (0%) 0
    Nausea 2/50 (4%) 2 1/65 (1.5%) 1 1/34 (2.9%) 1
    Pancreatic pseudocyst 0/50 (0%) 0 1/65 (1.5%) 2 0/34 (0%) 0
    Pancreatitis 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Pancreatitis acute 1/50 (2%) 2 0/65 (0%) 0 0/34 (0%) 0
    Small intestinal obstruction 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Vomiting 3/50 (6%) 3 1/65 (1.5%) 1 1/34 (2.9%) 2
    General disorders
    Device occlusion 1/50 (2%) 1 0/65 (0%) 0 0/34 (0%) 0
    Fatigue 1/50 (2%) 1 0/65 (0%) 0 1/34 (2.9%) 1
    Pyrexia 1/50 (2%) 1 3/65 (4.6%) 3 2/34 (5.9%) 2
    Thrombosis in device 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Hepatobiliary disorders
    Bile duct obstruction 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 2
    Cholangitis 0/50 (0%) 0 3/65 (4.6%) 3 1/34 (2.9%) 1
    Cholecystitis 1/50 (2%) 1 0/65 (0%) 0 1/34 (2.9%) 1
    Cholestasis 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Jaundice 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Immune system disorders
    Drug hypersensitivity 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Infections and infestations
    Abdominal sepsis 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Bacteraemia 1/50 (2%) 1 1/65 (1.5%) 1 0/34 (0%) 0
    Bacterial sepsis 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Bronchitis 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Cellulitis 2/50 (4%) 2 0/65 (0%) 0 0/34 (0%) 0
    Clostridium difficile colitis 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Device related infection 1/50 (2%) 1 0/65 (0%) 0 0/34 (0%) 0
    Escherichia bacteraemia 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Pneumonia 0/50 (0%) 0 2/65 (3.1%) 2 0/34 (0%) 0
    Renal abscess 1/50 (2%) 1 0/65 (0%) 0 0/34 (0%) 0
    Sepsis 1/50 (2%) 1 0/65 (0%) 0 0/34 (0%) 0
    Urinary tract infection 0/50 (0%) 0 0/65 (0%) 0 3/34 (8.8%) 3
    Injury, poisoning and procedural complications
    Infusion related reaction 1/50 (2%) 1 0/65 (0%) 0 0/34 (0%) 0
    Investigations
    C-reactive protein increased 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    International normalised ratio increased 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Metabolism and nutrition disorders
    Decreased appetite 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Dehydration 0/50 (0%) 0 1/65 (1.5%) 1 3/34 (8.8%) 3
    Hyperkalaemia 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Hyponatraemia 0/50 (0%) 0 1/65 (1.5%) 1 1/34 (2.9%) 1
    Hypovolaemia 0/50 (0%) 0 2/65 (3.1%) 2 0/34 (0%) 0
    Musculoskeletal and connective tissue disorders
    Back pain 1/50 (2%) 1 0/65 (0%) 0 0/34 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant ascites 1/50 (2%) 1 0/65 (0%) 0 0/34 (0%) 0
    Metastases to ovary 0/24 (0%) 0 0/23 (0%) 0 1/14 (7.1%) 1
    Tumour pain 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Nervous system disorders
    Cerebrovascular accident 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Syncope 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Psychiatric disorders
    Confusional state 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Renal and urinary disorders
    Nephrotic syndrome 1/50 (2%) 1 0/65 (0%) 0 0/34 (0%) 0
    Renal failure acute 0/50 (0%) 0 0/65 (0%) 0 2/34 (5.9%) 3
    Ureteric stenosis 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Acute respiratory failure 1/50 (2%) 1 0/65 (0%) 0 0/34 (0%) 0
    Interstitial lung disease 1/50 (2%) 1 0/65 (0%) 0 0/34 (0%) 0
    Pleural effusion 1/50 (2%) 1 0/65 (0%) 0 0/34 (0%) 0
    Pneumonitis 0/50 (0%) 0 2/65 (3.1%) 2 0/34 (0%) 0
    Pulmonary embolism 0/50 (0%) 0 1/65 (1.5%) 1 1/34 (2.9%) 1
    Respiratory failure 1/50 (2%) 1 0/65 (0%) 0 0/34 (0%) 0
    Vascular disorders
    Deep vein thrombosis 2/50 (4%) 2 0/65 (0%) 0 1/34 (2.9%) 1
    Hypotension 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Peripheral arterial occlusive disease 0/50 (0%) 0 1/65 (1.5%) 1 0/34 (0%) 0
    Phlebitis 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Phlebitis superficial 1/50 (2%) 1 0/65 (0%) 0 0/34 (0%) 0
    Venous thrombosis limb 0/50 (0%) 0 0/65 (0%) 0 1/34 (2.9%) 1
    Other (Not Including Serious) Adverse Events
    Phase 1: LY2603618 + Gemcitabine Phase 2: LY2603618 + Gemcitabine Phase 2: Gemcitabine
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 48/50 (96%) 64/65 (98.5%) 34/34 (100%)
    Blood and lymphatic system disorders
    Anaemia 23/50 (46%) 29 16/65 (24.6%) 21 10/34 (29.4%) 13
    Leukocytosis 3/50 (6%) 3 1/65 (1.5%) 1 0/34 (0%) 0
    Leukopenia 4/50 (8%) 5 8/65 (12.3%) 27 6/34 (17.6%) 10
    Lymphopenia 5/50 (10%) 6 4/65 (6.2%) 7 4/34 (11.8%) 4
    Neutropenia 16/50 (32%) 26 15/65 (23.1%) 49 10/34 (29.4%) 24
    Thrombocytopenia 23/50 (46%) 46 23/65 (35.4%) 63 15/34 (44.1%) 39
    Thrombocytosis 1/50 (2%) 1 0/65 (0%) 0 2/34 (5.9%) 5
    Cardiac disorders
    Sinus tachycardia 3/50 (6%) 3 0/65 (0%) 0 1/34 (2.9%) 1
    Gastrointestinal disorders
    Abdominal discomfort 3/50 (6%) 3 1/65 (1.5%) 2 0/34 (0%) 0
    Abdominal distension 4/50 (8%) 4 2/65 (3.1%) 3 2/34 (5.9%) 2
    Abdominal pain 12/50 (24%) 12 14/65 (21.5%) 19 5/34 (14.7%) 7
    Abdominal pain upper 2/50 (4%) 2 5/65 (7.7%) 5 1/34 (2.9%) 1
    Anorectal discomfort 0/50 (0%) 0 0/65 (0%) 0 2/34 (5.9%) 2
    Constipation 17/50 (34%) 22 21/65 (32.3%) 27 9/34 (26.5%) 10
    Diarrhoea 8/50 (16%) 10 21/65 (32.3%) 36 10/34 (29.4%) 15
    Dyspepsia 3/50 (6%) 3 4/65 (6.2%) 4 1/34 (2.9%) 1
    Flatulence 1/50 (2%) 1 4/65 (6.2%) 7 0/34 (0%) 0
    Gastritis 3/50 (6%) 3 1/65 (1.5%) 1 0/34 (0%) 0
    Haemorrhoids 2/50 (4%) 2 0/65 (0%) 0 2/34 (5.9%) 2
    Nausea 20/50 (40%) 25 27/65 (41.5%) 42 15/34 (44.1%) 21
    Steatorrhoea 0/50 (0%) 0 1/65 (1.5%) 1 2/34 (5.9%) 2
    Stomatitis 5/50 (10%) 9 13/65 (20%) 14 2/34 (5.9%) 2
    Vomiting 14/50 (28%) 16 19/65 (29.2%) 35 4/34 (11.8%) 5
    General disorders
    Asthenia 4/50 (8%) 5 10/65 (15.4%) 19 5/34 (14.7%) 8
    Chills 5/50 (10%) 6 9/65 (13.8%) 15 2/34 (5.9%) 2
    Fatigue 31/50 (62%) 50 22/65 (33.8%) 28 14/34 (41.2%) 19
    Influenza like illness 3/50 (6%) 3 3/65 (4.6%) 8 3/34 (8.8%) 3
    Infusion site pain 5/50 (10%) 10 0/65 (0%) 0 1/34 (2.9%) 4
    Irritability 3/50 (6%) 3 0/65 (0%) 0 0/34 (0%) 0
    Non-cardiac chest pain 3/50 (6%) 3 1/65 (1.5%) 1 1/34 (2.9%) 1
    Oedema peripheral 8/50 (16%) 9 19/65 (29.2%) 23 12/34 (35.3%) 16
    Pyrexia 15/50 (30%) 33 19/65 (29.2%) 23 11/34 (32.4%) 14
    Hepatobiliary disorders
    Hyperbilirubinaemia 2/50 (4%) 2 2/65 (3.1%) 2 4/34 (11.8%) 4
    Immune system disorders
    Drug hypersensitivity 5/50 (10%) 5 2/65 (3.1%) 5 0/34 (0%) 0
    Infections and infestations
    Oral candidiasis 4/50 (8%) 4 1/65 (1.5%) 2 1/34 (2.9%) 1
    Upper respiratory tract infection 3/50 (6%) 4 0/65 (0%) 0 0/34 (0%) 0
    Urinary tract infection 3/50 (6%) 3 2/65 (3.1%) 2 3/34 (8.8%) 3
    Injury, poisoning and procedural complications
    Infusion related reaction 3/50 (6%) 3 1/65 (1.5%) 1 0/34 (0%) 0
    Procedural pain 3/50 (6%) 4 0/65 (0%) 0 0/34 (0%) 0
    Investigations
    Alanine aminotransferase increased 10/50 (20%) 15 13/65 (20%) 18 6/34 (17.6%) 6
    Aspartate aminotransferase increased 11/50 (22%) 14 10/65 (15.4%) 15 5/34 (14.7%) 5
    Blood alkaline phosphatase increased 0/50 (0%) 0 5/65 (7.7%) 5 3/34 (8.8%) 3
    Blood lactate dehydrogenase increased 1/50 (2%) 1 2/65 (3.1%) 2 3/34 (8.8%) 3
    Gamma-glutamyltransferase increased 4/50 (8%) 4 12/65 (18.5%) 12 3/34 (8.8%) 3
    Haemoglobin decreased 0/50 (0%) 0 2/65 (3.1%) 2 2/34 (5.9%) 3
    Neutrophil count decreased 0/50 (0%) 0 3/65 (4.6%) 3 2/34 (5.9%) 6
    Platelet count decreased 0/50 (0%) 0 7/65 (10.8%) 11 1/34 (2.9%) 5
    Weight decreased 2/50 (4%) 3 7/65 (10.8%) 8 3/34 (8.8%) 3
    White blood cell count decreased 2/50 (4%) 2 2/65 (3.1%) 4 2/34 (5.9%) 8
    Metabolism and nutrition disorders
    Decreased appetite 16/50 (32%) 19 21/65 (32.3%) 22 5/34 (14.7%) 6
    Dehydration 3/50 (6%) 4 1/65 (1.5%) 1 3/34 (8.8%) 3
    Hyperglycaemia 3/50 (6%) 8 12/65 (18.5%) 13 4/34 (11.8%) 6
    Hyperkalaemia 0/50 (0%) 0 2/65 (3.1%) 2 3/34 (8.8%) 4
    Hypoalbuminaemia 1/50 (2%) 2 4/65 (6.2%) 4 3/34 (8.8%) 3
    Hypocalcaemia 1/50 (2%) 1 2/65 (3.1%) 4 6/34 (17.6%) 6
    Hypokalaemia 4/50 (8%) 4 1/65 (1.5%) 1 5/34 (14.7%) 6
    Hyponatraemia 3/50 (6%) 4 6/65 (9.2%) 7 5/34 (14.7%) 5
    Hypovolaemia 4/50 (8%) 8 0/65 (0%) 0 0/34 (0%) 0
    Vitamin d deficiency 3/50 (6%) 3 0/65 (0%) 0 1/34 (2.9%) 1
    Musculoskeletal and connective tissue disorders
    Arthralgia 3/50 (6%) 3 1/65 (1.5%) 1 0/34 (0%) 0
    Back pain 6/50 (12%) 6 9/65 (13.8%) 10 4/34 (11.8%) 4
    Muscular weakness 7/50 (14%) 9 2/65 (3.1%) 2 2/34 (5.9%) 2
    Musculoskeletal chest pain 3/50 (6%) 3 0/65 (0%) 0 2/34 (5.9%) 2
    Pain in extremity 5/50 (10%) 7 8/65 (12.3%) 9 1/34 (2.9%) 1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain 0/50 (0%) 0 0/65 (0%) 0 2/34 (5.9%) 3
    Nervous system disorders
    Dizziness 5/50 (10%) 5 5/65 (7.7%) 5 4/34 (11.8%) 4
    Dysgeusia 3/50 (6%) 5 5/65 (7.7%) 5 2/34 (5.9%) 2
    Headache 5/50 (10%) 7 7/65 (10.8%) 10 2/34 (5.9%) 2
    Peripheral sensory neuropathy 4/50 (8%) 4 7/65 (10.8%) 8 2/34 (5.9%) 4
    Psychiatric disorders
    Anxiety 4/50 (8%) 4 0/65 (0%) 0 3/34 (8.8%) 3
    Confusional state 1/50 (2%) 1 1/65 (1.5%) 1 2/34 (5.9%) 2
    Depression 6/50 (12%) 7 2/65 (3.1%) 2 3/34 (8.8%) 4
    Insomnia 7/50 (14%) 9 4/65 (6.2%) 4 6/34 (17.6%) 8
    Renal and urinary disorders
    Pollakiuria 3/50 (6%) 3 0/65 (0%) 0 0/34 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Cough 10/50 (20%) 12 7/65 (10.8%) 7 5/34 (14.7%) 6
    Dysphonia 0/50 (0%) 0 2/65 (3.1%) 2 2/34 (5.9%) 2
    Dyspnoea 8/50 (16%) 11 12/65 (18.5%) 13 2/34 (5.9%) 2
    Dyspnoea exertional 4/50 (8%) 7 2/65 (3.1%) 2 1/34 (2.9%) 1
    Epistaxis 5/50 (10%) 5 1/65 (1.5%) 2 0/34 (0%) 0
    Skin and subcutaneous tissue disorders
    Alopecia 2/50 (4%) 2 7/65 (10.8%) 8 5/34 (14.7%) 6
    Decubitus ulcer 1/50 (2%) 1 4/65 (6.2%) 4 0/34 (0%) 0
    Dermatitis acneiform 4/50 (8%) 5 2/65 (3.1%) 2 0/34 (0%) 0
    Hyperhidrosis 3/50 (6%) 3 1/65 (1.5%) 1 0/34 (0%) 0
    Pruritus 1/50 (2%) 1 4/65 (6.2%) 6 2/34 (5.9%) 2
    Vascular disorders
    Deep vein thrombosis 1/50 (2%) 1 4/65 (6.2%) 4 3/34 (8.8%) 3
    Flushing 6/50 (12%) 8 0/65 (0%) 0 0/34 (0%) 0
    Hypertension 1/50 (2%) 1 3/65 (4.6%) 3 3/34 (8.8%) 3
    Hypotension 5/50 (10%) 5 3/65 (4.6%) 3 5/34 (14.7%) 5
    Thrombophlebitis superficial 0/50 (0%) 0 4/65 (6.2%) 4 0/34 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Chief Medical Officer
    Organization Eli Lilly and Company
    Phone 800-545-5979
    Email
    Responsible Party:
    Eli Lilly and Company
    ClinicalTrials.gov Identifier:
    NCT00839332
    Other Study ID Numbers:
    • 12096
    • I2I-MC-JMMC
    First Posted:
    Feb 9, 2009
    Last Update Posted:
    Apr 17, 2018
    Last Verified:
    Mar 1, 2018