A Phase 1/2 interventional study of LY2603618 and Gemcitabine in Pancreatic Neoplasms, sponsored by Eli Lilly and Company. Completed at 30 sites in 6 countries. Open to participants aged 18 Years to 85 Years. Per ClinicalTrials.gov, last updated 2018-04-17.
Sponsored by Eli Lilly and Company · Phase 1/2, Interventional, and Treatment
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.
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.
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Exclusion Criteria:
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
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
Also known as: Gemzar, LY188011
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
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
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.
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.
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.
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.
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
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
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
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
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
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
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
| Milestone | Phase 1: LY2603618 + Gemcitabine | Phase 2: LY2603618 + Gemcitabine | Phase 2: Gemcitabine |
|---|---|---|---|
| Started | 50 | 0 | 0 |
| Received at least 1 dose of study drug | 50 | 0 | 0 |
| Completed | 0 | 0 | 0 |
| Not completed | 50 | 0 | 0 |
| Withdrew: Disease progression | 38 | 0 | 0 |
| Withdrew: Adverse event | 6 | 0 | 0 |
| Withdrew: Withdrawal by subject | 4 | 0 | 0 |
| Withdrew: Physician decision | 2 | 0 | 0 |
| Milestone | Phase 1: LY2603618 + Gemcitabine | Phase 2: LY2603618 + Gemcitabine | Phase 2: Gemcitabine |
|---|---|---|---|
| Started | 0 | 68 | 39 |
| Received at least 1 dose of study drug | 0 | 65 | 34 |
| Completed | 0 | 0 | 0 |
| Not completed | 0 | 68 | 39 |
| Withdrew: Protocol violation | 0 | 1 | 0 |
| Withdrew: Disease progression | 0 | 46 | 21 |
| Withdrew: Adverse event | 0 | 8 | 6 |
| Withdrew: Death | 0 | 4 | 2 |
| Withdrew: Withdrawal by subject | 0 | 5 | 8 |
| Withdrew: Physician decision | 0 | 4 | 1 |
| Withdrew: Lost to follow-up | 0 | 0 | 1 |
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 \[ng/mL\]).
| milligrams (mg) | Phase 1: LY2603618 + Gemcitabine |
|---|---|
| Phase 1: Determine the Recommended Phase 2 Dose for LY2603618 When Administered After Gemcitabine | 230 |
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.
| months | Phase 2: LY2603618 + Gemcitabine | Phase 2: Gemcitabine |
|---|---|---|
| Phase 2: Overall Survival (OS) | 7.8 (5.0 to 11.1) | 8.3 (5.1 to 14.1) |
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.
| nanograms per milliliter (ng/mL) | Phase 1: LY2603618 + Gemcitabine |
|---|---|
| 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 |
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.
| ng/mL | Phase 2: LY2603618 + Gemcitabine |
|---|---|
| Cycle 1 /Day 2 | 3170 ± 50 |
| Cycle 1 /Day 16 | 3410 ± 50 |
| Cycle 2 /Day 2 | 2390 ± 54 |
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.
| nanogram*hour/milliliter (ng*h/mL) | Phase 1: LY2603618 + Gemcitabine |
|---|---|
| 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 |
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.
| ng*h/mL | Phase 2: LY2603618 + Gemcitabine |
|---|---|
| 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 |
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.
| months | Phase 2: LY2603618 + Gemcitabine | Phase 2: Gemcitabine |
|---|---|---|
| Phase 2: Progression-free Survival (PFS) | 3.5 (2.1 to 3.6) | 5.6 (2.6 to 7.6) |
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.
| percentage of participants | Phase 2: LY2603618 + Gemcitabine | Phase 2: Gemcitabine |
|---|---|---|
| Phase 2: Overall Response Rate | 21.5 (12.3 to 33.5) | 8.8 (1.9 to 23.7) |
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.
| percentage of participants | Phase 2: LY2603618 + Gemcitabine | Phase 2: Gemcitabine |
|---|---|---|
| Phase 2: Clinical Benefit Rate | 55.4 (42.5 to 67.7) | 64.7 (46.5 to 80.3) |
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.
| Participants | Phase 1: LY2603618 + Gemcitabine |
|---|---|
| Total deaths | 5 |
| Deaths within 30 days of last dose of study drug | 4 |
| Deaths during the follow-up period | 1 |
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.
| months | Phase 2: LY2603618 + Gemcitabine | Phase 2: Gemcitabine |
|---|---|---|
| Phase 2: Duration of Response | 3.5 (1.9 to 5.8) | 6.0 (3.7 to 6.8) |
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.
| Participants | Phase 1: LY2603618 + Gemcitabine |
|---|---|
| 70 mg/m^2, <=30 msec | 2 |
| 70 mg/m^2, >30-60 msec | 1 |
| 70 mg/m^2, >60 msec | 0 |
| 105 mg/m^2, <=30 msec | 2 |
| 105 mg/m^2, >30-60 msec | 0 |
| 105 mg/m^2, >60 msec | 0 |
| 150 mg/m^2, <=30 msec | 6 |
| 150 mg/m^2, >30-60 msec | 1 |
| 150 mg/m^2, >60 msec | 0 |
| 200 mg/m^2, <=30 msec | 11 |
| 200 mg/m^2, >30-60 msec | 0 |
| 200 mg/m^2, >60 msec | 0 |
| 250 mg/m^2, <=30 msec | 6 |
| 250 mg/m^2, >30-60 msec | 0 |
| 250 mg/m^2, >60 msec | 0 |
| 200 mg (flat dose), <=30 msec | 9 |
| 200 mg (flat dose), >30-60 msec | 1 |
| 200 mg (flat dose), >60 msec | 0 |
| 230 mg (flat dose), <=30 msec | 8 |
| 230 mg (flat dose), >30-60 msec | 2 |
| 230 mg (flat dose), >60 msec | 0 |
| Total, <=30 msec | 44 |
| Total, >30-60 msec | 5 |
| Total, >60 msec | 0 |
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.
| Participants | Phase 2: LY2603618 + Gemcitabine |
|---|---|
| <=30 msec | 55 |
| >30-60 msec | 5 |
| >60 msec | 0 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Phase 1: LY2603618 + Gemcitabine | — | 21/50 (42%) | 48/50 (96%) |
| Phase 2: LY2603618 + Gemcitabine | — | 27/65 (41.5%) | 64/65 (98.5%) |
| Phase 2: Gemcitabine | — | 18/34 (52.9%) | 34/34 (100%) |
| Event | Phase 1: LY2603618 + Gemcitabine | Phase 2: LY2603618 + Gemcitabine | Phase 2: Gemcitabine |
|---|---|---|---|
| Urinary tract infectionInfections and infestations | 0/50 | 0/65 | 3/34 |
| DehydrationMetabolism and nutrition disorders | 0/50 | 1/65 | 3/34 |
| Metastases to ovaryNeoplasms benign, malignant and unspecified (incl cysts and polyps) | 0/24 | 0/23 | 1/14 |
| ThrombocytopeniaBlood and lymphatic system disorders | 3/50 | 0/65 | 0/34 |
| VomitingGastrointestinal disorders | 3/50 | 1/65 | 1/34 |
| Abdominal painGastrointestinal disorders | 0/50 | 2/65 | 2/34 |
| PyrexiaGeneral disorders | 1/50 | 3/65 | 2/34 |
| Renal failure acuteRenal and urinary disorders | 0/50 | 0/65 | 2/34 |
| CholangitisHepatobiliary disorders | 0/50 | 3/65 | 1/34 |
| NeutropeniaBlood and lymphatic system disorders | 2/50 | 0/65 | 0/34 |
| Event | Phase 1: LY2603618 + Gemcitabine | Phase 2: LY2603618 + Gemcitabine | Phase 2: Gemcitabine |
|---|---|---|---|
| FatigueGeneral disorders | 31/50 | 22/65 | 14/34 |
| AnaemiaBlood and lymphatic system disorders | 23/50 | 16/65 | 10/34 |
| ThrombocytopeniaBlood and lymphatic system disorders | 23/50 | 23/65 | 15/34 |
| NauseaGastrointestinal disorders | 20/50 | 27/65 | 15/34 |
| Oedema peripheralGeneral disorders | 8/50 | 19/65 | 12/34 |
| ConstipationGastrointestinal disorders | 17/50 | 21/65 | 9/34 |
| PyrexiaGeneral disorders | 15/50 | 19/65 | 11/34 |
| DiarrhoeaGastrointestinal disorders | 8/50 | 21/65 | 10/34 |
| Decreased appetiteMetabolism and nutrition disorders | 16/50 | 21/65 | 5/34 |
| NeutropeniaBlood and lymphatic system disorders | 16/50 | 15/65 | 10/34 |
Participants who received at least 1 dose of study drug.
| Age, Continuous(years) | Phase 1: LY2603618 + Gemcitabine | Phase 2: LY2603618 + Gemcitabine | Phase 2: Gemcitabine | Total |
|---|---|---|---|---|
| Mean | 59.0 ± 12.2 | 64.3 ± 8.3 | 64.4 ± 10.1 | 62.54 ± 11.8 |
| Sex: Female, Male(Participants) | Phase 1: LY2603618 + Gemcitabine | Phase 2: LY2603618 + Gemcitabine | Phase 2: Gemcitabine | Total |
|---|---|---|---|---|
| Female | 24 | 23 | 14 | 61 |
| Male | 26 | 42 | 20 | 88 |
| Race/Ethnicity, Customized(Participants) | Phase 1: LY2603618 + Gemcitabine | Phase 2: LY2603618 + Gemcitabine | Phase 2: Gemcitabine | Total |
|---|---|---|---|---|
| White | 46 | 62 | 32 | 140 |
| Black or African American | 1 | 2 | 2 | 5 |
| American Indian or Alaska Native | 0 | 1 | 0 | 1 |
| Asian | 3 | 0 | 0 | 3 |
| Region of Enrollment(Participants) | Phase 1: LY2603618 + Gemcitabine | Phase 2: LY2603618 + Gemcitabine | Phase 2: Gemcitabine | Total |
|---|---|---|---|---|
| United States | 32 | 27 | 14 | 73 |
| Spain | 18 | 12 | 5 | 35 |
| Romania | 0 | 2 | 1 | 3 |
| Germany | 0 | 17 | 9 | 26 |
| Netherlands | 0 | 3 | 2 | 5 |
| Italy | 0 | 3 | 2 | 5 |
| Poland | 0 | 1 | 1 | 2 |
| Initial Pathological Diagnosis(Participants) | Phase 1: LY2603618 + Gemcitabine | Phase 2: LY2603618 + Gemcitabine | Phase 2: Gemcitabine | Total |
|---|---|---|---|---|
| Adenocarcinoma, Pancreas | 10 | 65 | 34 | 109 |
| Adenocarcinoma, Colon | 7 | 0 | 0 | 7 |
| Carcinoma, Breast | 4 | 0 | 0 | 4 |
| Carcinoma, Non-Small Cell, Lung NOS | 3 | 0 | 0 | 3 |
| Adenocarcinoma, Cervix | 2 | 0 | 0 | 2 |
| Adenocarcinoma, Rectum | 2 | 0 | 0 | 2 |
| Carcinoma, Endometrium | 2 | 0 | 0 | 2 |
| Carcinoma, Infiltrating Ductal, Breast | 2 | 0 | 0 | 2 |
| Carcinoma, Renal Cell | 2 | 0 | 0 | 2 |
| Sarcoma, Leiomyosarcoma, Abdomen (Non-Gist) | 2 | 0 | 0 | 2 |
| Squamous Cell Carcinoma, Head and Neck | 2 | 0 | 0 | 2 |
| Ampulla of Pancreas | 1 | 0 | 0 | 1 |
| Carcinoma, Head and Neck | 1 | 0 | 0 | 1 |
| Carcinoma, Ovarian | 1 | 0 | 0 | 1 |
| Carcinoma, Peritoneal | 1 | 0 | 0 | 1 |
| Carcinoma, Small Cell, Lung | 1 | 0 | 0 | 1 |
| Carcinoma, Transitional Cell, Urothelium | 1 | 0 | 0 | 1 |
| Ewing's Sarcoma | 1 | 0 | 0 | 1 |
| Lymphoma, Non-Hodgkin's Lymphoma | 1 | 0 | 0 | 1 |
| Mesothelioma, Pleural, Malignant | 1 | 0 | 0 | 1 |
| Ovarian Adenocarcinoma | 1 | 0 | 0 | 1 |
| Squamous Cell Carcinoma, Cervix | 1 | 0 | 0 | 1 |
| Tumor | 1 | 0 | 0 | 1 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status(Participants) | Phase 1: LY2603618 + Gemcitabine | Phase 2: LY2603618 + Gemcitabine | Phase 2: Gemcitabine | Total |
|---|---|---|---|---|
| ECOG Status 0 | 19 | 28 | 14 | 61 |
| ECOG Status 1 | 31 | 31 | 17 | 79 |
| ECOG Status 2 | 0 | 6 | 3 | 9 |
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