Pancreatic Neoplasms
Conditions
Keywords
Pancreas, metastatic cancer, advanced cancer, Pancreatic cancer
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.
Detailed description
Phase 1 included a dose escalation of LY2603618 doses from 70 milligrams/meter squared (mg/m\^2) to 250 mg/m\^2 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.
Interventions
DRUGLY2603618
DRUGGemcitabine
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 \[ng/mL\]). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Germany, Italy, Netherlands, Romania, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: LY2603618 + Gemcitabine 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. | 50 |
| Phase 2: LY2603618 + Gemcitabine 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. | 65 |
| Phase 2: Gemcitabine 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. | 34 |
| Total | 149 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Phase 1 | Adverse Event | 6 | 0 | 0 |
| Phase 1 | Disease Progression | 38 | 0 | 0 |
| Phase 1 | Physician Decision | 2 | 0 | 0 |
| Phase 1 | Withdrawal by Subject | 4 | 0 | 0 |
| Phase 2 | Adverse Event | 0 | 8 | 6 |
| Phase 2 | Death | 0 | 4 | 2 |
| Phase 2 | Disease Progression | 0 | 46 | 21 |
| Phase 2 | Lost to Follow-up | 0 | 0 | 1 |
| Phase 2 | Physician Decision | 0 | 4 | 1 |
| Phase 2 | Protocol Violation | 0 | 1 | 0 |
| Phase 2 | Withdrawal by Subject | 0 | 5 | 8 |
Baseline characteristics
| Characteristic | Phase 1: LY2603618 + Gemcitabine | Phase 2: LY2603618 + Gemcitabine | Phase 2: Gemcitabine | Total |
|---|---|---|---|---|
| Age, Continuous | 59.0 years STANDARD_DEVIATION 12.2 | 64.3 years STANDARD_DEVIATION 8.3 | 64.4 years STANDARD_DEVIATION 10.1 | 62.54 years STANDARD_DEVIATION 11.8 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG Status 0 | 19 Participants | 28 Participants | 14 Participants | 61 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG Status 1 | 31 Participants | 31 Participants | 17 Participants | 79 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG Status 2 | 0 Participants | 6 Participants | 3 Participants | 9 Participants |
| Initial Pathological Diagnosis Adenocarcinoma, Cervix | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Initial Pathological Diagnosis Adenocarcinoma, Colon | 7 Participants | 0 Participants | 0 Participants | 7 Participants |
| Initial Pathological Diagnosis Adenocarcinoma, Pancreas | 10 Participants | 65 Participants | 34 Participants | 109 Participants |
| Initial Pathological Diagnosis Adenocarcinoma, Rectum | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Initial Pathological Diagnosis Ampulla of Pancreas | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Carcinoma, Breast | 4 Participants | 0 Participants | 0 Participants | 4 Participants |
| Initial Pathological Diagnosis Carcinoma, Endometrium | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Initial Pathological Diagnosis Carcinoma, Head and Neck | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Carcinoma, Infiltrating Ductal, Breast | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Initial Pathological Diagnosis Carcinoma, Non-Small Cell, Lung NOS | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Initial Pathological Diagnosis Carcinoma, Ovarian | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Carcinoma, Peritoneal | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Carcinoma, Renal Cell | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Initial Pathological Diagnosis Carcinoma, Small Cell, Lung | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Carcinoma, Transitional Cell, Urothelium | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Ewing's Sarcoma | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Lymphoma, Non-Hodgkin's Lymphoma | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Mesothelioma, Pleural, Malignant | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Ovarian Adenocarcinoma | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Sarcoma, Leiomyosarcoma, Abdomen (Non-Gist) | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Initial Pathological Diagnosis Squamous Cell Carcinoma, Cervix | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Initial Pathological Diagnosis Squamous Cell Carcinoma, Head and Neck | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Initial Pathological Diagnosis Tumor | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized White | 46 Participants | 62 Participants | 32 Participants | 140 Participants |
| Region of Enrollment Germany | 0 Participants | 17 Participants | 9 Participants | 26 Participants |
| Region of Enrollment Italy | 0 Participants | 3 Participants | 2 Participants | 5 Participants |
| Region of Enrollment Netherlands | 0 Participants | 3 Participants | 2 Participants | 5 Participants |
| Region of Enrollment Poland | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Region of Enrollment Romania | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment Spain | 18 Participants | 12 Participants | 5 Participants | 35 Participants |
| Region of Enrollment United States | 32 Participants | 27 Participants | 14 Participants | 73 Participants |
| Sex: Female, Male Female | 24 Participants | 23 Participants | 14 Participants | 61 Participants |
| Sex: Female, Male Male | 26 Participants | 42 Participants | 20 Participants | 88 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 48 / 50 | 64 / 65 | 34 / 34 |
| serious Total, serious adverse events | 21 / 50 | 27 / 65 | 18 / 34 |
Outcome results
Primary
Phase 1: Determine the Recommended Phase 2 Dose for LY2603618 When Administered After Gemcitabine
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
Population: Phase 1 participants who received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Determine the Recommended Phase 2 Dose for LY2603618 When Administered After Gemcitabine | 230 milligrams (mg) |
Primary
Phase 2: Overall Survival (OS)
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
Population: Phase 2 participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Overall Survival (OS) | 7.8 months |
| Phase 2: Gemcitabine | Phase 2: Overall Survival (OS) | 8.3 months |
Secondary
Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618
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.
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 105 mg/m^2, Cycle 1 /Day 2 | 40500 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 23 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 200 mg/m^2, Cycle 2 /Day 2 | 44300 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 39 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 105 mg/m^2, Cycle 2 /Day 2 | 79600 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 19 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 70 mg/m^2, Cycle 1 /Day 2 | 21300 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 24 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 70 mg/m^2, Cycle 1 /Day 16 | 21200 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 27 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 70 mg/m^2, Cycle 2 /Day 2 | 19900 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 24 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 105 mg/m^2, Cycle 1 /Day 16 | 50100 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 32 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 105 mg/m^2, Cycle 2 /Day 2 | 49800 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 4 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 150 mg/m^2, Cycle 1 /Day 2 | 32200 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 27 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 150 mg/m^2, Cycle 1 /Day 16 | 40000 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 29 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 150 mg/m^2, Cycle 2 /Day 2 | 31000 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 42 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 200 mg/m^2, Cycle 1 /Day 2 | 40200 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 42 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 200 mg/m^2, Cycle 1 /Day 16 | 39800 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 36 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 250 mg/m^2, Cycle 1 /Day 2 | 88800 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 27 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 250 mg/m^2, Cycle 1 /Day 16 | 61000 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 63 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 250 mg/m^2, Cycle 2 /Day 2 | 40000 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 112 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 200 mg (flat), Cycle 1 /Day 2 | 22900 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 77 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 200 mg (flat), Cycle 1 /Day 16 | 28700 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 63 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 200 mg (flat), Cycle 2 /Day 2 | 23800 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 62 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 230 mg (flat), Cycle 1 /Day 2 | 32400 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 38 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 230 mg (flat), Cycle 1 /Day 16 | 32300 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 22 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), 230 mg (flat), Cycle 2 /Day 2 | 32500 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 24 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 70 mg/m^2, Cycle 1 /Day 2 | 24600 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 28 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 70 mg/m^2, Cycle 1 /Day 16 | 27500 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 21 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 70 mg/m^2, Cycle 2 /Day 2 | 25800 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 29 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 105 mg/m^2, Cycle 1 /Day 2 | 65800 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 53 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 105 mg/m^2, Cycle 1 /Day 16 | 75500 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 46 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 150 mg/m^2, Cycle 1 /Day 2 | 41600 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 31 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 150 mg/m^2, Cycle 1 /Day 16 | 52000 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 38 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 150 mg/m^2, Cycle 2 /Day 2 | 39800 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 45 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 200 mg/m^2, Cycle 1 /Day 2 | 44300 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 85 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 200 mg/m^2, Cycle 1 /Day 16 | 55300 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 51 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 200 mg/m^2, Cycle 2 /Day 2 | 55600 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 51 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 250 mg/m^2, Cycle 1 /Day 2 | 140000 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 37 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 250 mg/m^2, Cycle 1 /Day 16 | 98200 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 139 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 250 mg/m^2, Cycle 2 /Day 2 | 60400 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 178 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 200 mg (flat), Cycle 1 /Day 2 | 33100 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 101 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 200 mg (flat), Cycle 1 /Day 16 | 42600 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 88 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 200 mg (flat), Cycle 2 /Day 2 | 32400 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 85 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 230 mg (flat), Cycle 1 /Day 2 | 43000 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 50 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 230 mg (flat), Cycle 1 /Day 16 | 51900 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 50 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), 230 mg (flat), Cycle 2 /Day 2 | 45900 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 26 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 70 mg/m^2, Cycle 1 /Day 2 | 24900 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 29 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 70 mg/m^2, Cycle 1 /Day 16 | 28600 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 19 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 70 mg/m^2, Cycle 2 /Day 2 | 27100 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 31 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 105 mg/m^2, Cycle 1 /Day 2 | 78600 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 68 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 105 mg/m^2, Cycle 1 /Day 16 | 79800 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 51 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 105 mg/m^2, Cycle 2 /Day 2 | 88800 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 25 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 150 mg/m^2, Cycle 1 /Day 2 | 42800 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 33 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 150 mg/m^2, Cycle 1 /Day 16 | 54600 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 43 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 150 mg/m^2, Cycle 2 /Day 2 | 41000 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 46 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 200 mg/m^2, Cycle 1 /Day 2 | 60300 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 58 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 200 mg/m^2, Cycle 1 /Day 16 | 56800 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 54 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 200 mg/m^2, Cycle 2 /Day 2 | 65400 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 49 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 250 mg/m^2, Cycle 1 /Day 2 | 153000 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 41 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 250 mg/m^2, Cycle 1 /Day 16 | 101000 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 141 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 250 mg/m^2, Cycle 2 /Day 2 | 70500 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 216 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 200 mg (flat), Cycle 1 /Day 2 | 35200 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 117 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 200 mg (flat), Cycle 1 /Day 16 | 45700 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 93 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 200 mg (flat), Cycle 2 /Day 2 | 34400 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 93 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 230 mg (flat), Cycle 1 /Day 2 | 45200 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 50 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 230 mg (flat), Cycle 1 /Day 16 | 57700 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 58 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), 230 mg (flat), Cycle 2 /Day 2 | 48000 nanogram*hour/milliliter (ng*h/mL) | Geometric Coefficient of Variation 26 |
Secondary
Phase 1: Electrocardiogram QTc Prolongation
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
Population: Phase 1 participants who received at least 1 dose of LY2603618 and had evaluable ECG data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 150 mg/m^2, <=30 msec | 6 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 70 mg/m^2, <=30 msec | 2 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 70 mg/m^2, >30-60 msec | 1 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 70 mg/m^2, >60 msec | 0 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 105 mg/m^2, <=30 msec | 2 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 105 mg/m^2, >30-60 msec | 0 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 105 mg/m^2, >60 msec | 0 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 150 mg/m^2, >30-60 msec | 1 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 150 mg/m^2, >60 msec | 0 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 200 mg/m^2, <=30 msec | 11 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 200 mg/m^2, >30-60 msec | 0 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 200 mg/m^2, >60 msec | 0 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 250 mg/m^2, <=30 msec | 6 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 250 mg/m^2, >30-60 msec | 0 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 250 mg/m^2, >60 msec | 0 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 200 mg (flat dose), <=30 msec | 9 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 200 mg (flat dose), >30-60 msec | 1 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 200 mg (flat dose), >60 msec | 0 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 230 mg (flat dose), <=30 msec | 8 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 230 mg (flat dose), >30-60 msec | 2 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | 230 mg (flat dose), >60 msec | 0 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | Total, <=30 msec | 44 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | Total, >30-60 msec | 5 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Electrocardiogram QTc Prolongation | Total, >60 msec | 0 Participants |
Secondary
Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618
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.
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 230 mg (flat dose), Cycle 1 /Day 16 | 4980 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 35 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 70 mg/m^2, Cycle 1 /Day 2 | 3530 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 23 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 70 mg/m^2, Cycle 1 /Day 16 | 3360 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 26 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 70 mg/m^2, Cycle 2 /Day 2 | 3100 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 12 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 105 mg/m^2, Cycle 1 /Day 2 | 4890 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 25 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 105 mg/m^2, Cycle 1 /Day 16 | 5170 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 38 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 105 mg/m^2, Cycle 2 /Day 2 | 5360 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 23 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 150 mg/m^2, Cycle 1 /Day 2 | 4280 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 29 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 150 mg/m^2, Cycle 1 /Day 16 | 5040 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 38 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 150 mg/m^2, Cycle 2 /Day 2 | 4370 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 38 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 200 mg/m^2, Cycle 1 /Day 2 | 4870 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 63 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 200 mg/m^2, Cycle 1 /Day 16 | 5360 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 40 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 200 mg/m^2, Cycle 2 /Day 2 | 5290 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 40 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 250 mg/m^2, Cycle 1 /Day 2 | 7990 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 25 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 250 mg/m^2, Cycle 1 /Day 16 | 7990 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 6 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 250 mg/m^2, Cycle 2 /Day 2 | 5290 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 35 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 200 mg (flat dose), Cycle 1 /Day 2 | 3440 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 65 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 200 mg (flat dose), Cycle 1 /Day 16 | 3470 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 61 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 200 mg (flat dose), Cycle 2 /Day 2 | 3640 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 45 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 230 mg (flat dose), Cycle 1 /Day 2 | 4820 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 72 |
| Phase 1: LY2603618 + Gemcitabine | Phase 1: Maximum Plasma Concentration (Cmax) of Gemcitabine, 2',2'-Difluorodeoxyuridine (dFdU), and LY2603618 | 230 mg (flat dose), Cycle 2 /Day 2 | 3830 nanograms per milliliter (ng/mL) | Geometric Coefficient of Variation 26 |
Secondary
Phase 2: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618
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.
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), Cycle 1 /Day 2 | 23200 ng*h/mL | Geometric Coefficient of Variation 68 |
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), Cycle 1 /Day 16 | 23700 ng*h/mL | Geometric Coefficient of Variation 60 |
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-24), Cycle 2 /Day 2 | 19800 ng*h/mL | Geometric Coefficient of Variation 63 |
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), Cycle 1 /Day 2 | 22200 ng*h/mL | Geometric Coefficient of Variation 73 |
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), Cycle 1 /Day 16 | 20800 ng*h/mL | Geometric Coefficient of Variation 78 |
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-tlast), Cycle 2 /Day 2 | 20100 ng*h/mL | Geometric Coefficient of Variation 64 |
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), Cycle 1 /Day 2 | 29400 ng*h/mL | Geometric Coefficient of Variation 84 |
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), Cycle 1 /Day 16 | 29100 ng*h/mL | Geometric Coefficient of Variation 74 |
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Area Under the Plasma Concentration Versus Time Curve (AUC) of Gemcitabine, dFdU, and LY2603618 | AUC(0-inf), Cycle 2 /Day 2 | 23300 ng*h/mL | Geometric Coefficient of Variation 69 |
Secondary
Phase 2: Clinical Benefit Rate
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
Population: Phase 2 participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Clinical Benefit Rate | 55.4 percentage of participants |
| Phase 2: Gemcitabine | Phase 2: Clinical Benefit Rate | 64.7 percentage of participants |
Secondary
Phase 2: Duration of Response
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
Population: Phase 2 participants who received at least 1 dose of study drug and had a confirmed response (CR or PR).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Duration of Response | 3.5 months |
| Phase 2: Gemcitabine | Phase 2: Duration of Response | 6.0 months |
Secondary
Phase 2: Electrocardiogram QTc Prolongation
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
Population: Phase 2 participants who received at least 1 dose of LY2603618 and had evaluable ECG data.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Electrocardiogram QTc Prolongation | <=30 msec | 55 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Electrocardiogram QTc Prolongation | >30-60 msec | 5 Participants |
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Electrocardiogram QTc Prolongation | >60 msec | 0 Participants |
Secondary
Phase 2: Maximum Plasma Concentration (Cmax) of Gemcitabine, dFdU, and LY2603618
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.
Population: 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 | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Maximum Plasma Concentration (Cmax) of Gemcitabine, dFdU, and LY2603618 | Cycle 1 /Day 2 | 3170 ng/mL | Geometric Coefficient of Variation 50 |
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Maximum Plasma Concentration (Cmax) of Gemcitabine, dFdU, and LY2603618 | Cycle 1 /Day 16 | 3410 ng/mL | Geometric Coefficient of Variation 50 |
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Maximum Plasma Concentration (Cmax) of Gemcitabine, dFdU, and LY2603618 | Cycle 2 /Day 2 | 2390 ng/mL | Geometric Coefficient of Variation 54 |
Secondary
Phase 2: Overall Response Rate
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
Population: Phase 2 participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Overall Response Rate | 21.5 percentage of participants |
| Phase 2: Gemcitabine | Phase 2: Overall Response Rate | 8.8 percentage of participants |
Secondary
Phase 2: Progression-free Survival (PFS)
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
Population: Phase 2 participants who were randomized.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1: LY2603618 + Gemcitabine | Phase 2: Progression-free Survival (PFS) | 3.5 months |
| Phase 2: Gemcitabine | Phase 2: Progression-free Survival (PFS) | 5.6 months |
Other Pre-specified
Number of Deaths During the Phase 1 Post-study 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.
Time frame: Phase 1: Time of last dose of study drug through the end of the follow-up period
Population: Participants enrolled in Phase 1.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1: LY2603618 + Gemcitabine | Number of Deaths During the Phase 1 Post-study Period | Total deaths | 5 Participants |
| Phase 1: LY2603618 + Gemcitabine | Number of Deaths During the Phase 1 Post-study Period | Deaths within 30 days of last dose of study drug | 4 Participants |
| Phase 1: LY2603618 + Gemcitabine | Number of Deaths During the Phase 1 Post-study Period | Deaths during the follow-up period | 1 Participants |