Phase 2 Study of Gemcitabine or Gemcitabine + Enzastaurin in Participants With Advanced or Metastatic Pancreatic Cancer

• Sponsor: Eli Lilly and Company (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00267020
• Collaborator: (none)
• Enrollment: 130
• Location: 1
• Arms: 2
• Duration (Months): 29
• Patients Per Site Per Month: 4.5

Study Details

Study Description

Brief Summary

The purpose of this research study is to determine the effects and toxicity of gemcitabine alone or gemcitabine plus enzastaurin in participants with pancreatic cancer.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Neoplasm	Drug: enzastaurin; Drug: gemcitabine	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 130 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized, Open-Label Phase 2 Study of 2 Regimens, Gemcitabine Plus Enzastaurin and Single-Agent Gemcitabine, in Patients With Locally Advanced or Metastatic Pancreatic Cancer
• Study Start Date: Dec 1, 2005
• Actual Primary Completion Date: May 1, 2008
• Actual Study Completion Date: May 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Enzastaurin+Gemcitabine	Drug: enzastaurin; 1200 milligrams (mg) loading dose then 500 mg, orally, daily, six 28-day cycles; Other Names: LY317615 ; Drug: gemcitabine; 1000 milligrams/square meter (mg/m^2), intravenously on Days 1, 8 and 15 per cycle, six 28-day cycles; Other Names: LY188011 Gemzar
Active Comparator: Gemcitabine	Drug: gemcitabine; 1000 milligrams/square meter (mg/m^2), intravenously on Days 1, 8 and 15 per cycle, six 28-day cycles; Other Names: LY188011 Gemzar

Outcome Measures

Primary Outcome Measures

1. Overall Survival (OS) [Randomization to the date of death from any cause up to 27.7 months]

   OS was the duration from randomization to death. OS was censored at the last contact for participants who were alive, at the cut-off date.

Secondary Outcome Measures

1. Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Response Rate) [Randomization to measured progressive disease (PD) up to 19.9 months]

   Response rate was defined as percentage of responders (best study response recorded as CR or PR) from the qualified number of participants for tumor response analysis. Response defined using Response Evaluation Criteria In Solid Tumors (RECIST, v1.0) criteria: CR was disappearance of all target lesions for at least 4 weeks. PR was at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of LD. Percentage of participants was calculated as: (The number of responders with CR or PR/ The number of participants qualified for tumor response analysis) × 100.

2. Progression Free Survival (PFS) [Randomization to measured PD or death from any cause up to 21.6 months]

   PFS was defined as the time from the date of randomization to the first date of documented progressive disease (PD) or death due to any cause, whichever occurred first. PFS was censored at the date of the last assessment visit for participants who were still alive at data cut-off and who had not had documented progressive disease. Participants who started a new treatment before progression were censored as of the date of the start of new treatment.

3. Duration of Response [Time of response to PD or death from any cause up to 19.9 months]

   The duration of a complete response (CR) or partial response (PR) was defined, using the Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria, as the time from first objective status assessment of CR or PR to the first time of disease progression or death as a result of any cause. Using the Response Evaluation Criteria in Solid Tumors (RECIST V1.0) criteria, CR was defined as the disappearance of all tumor lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of LD. Duration of response was censored at the date of the last assessment visit for responders who were still alive at data cut-off and had no documented progressive disease (PD).

4. Change in Scores From Baseline (Improved, Stable or Worsened) to End of Study in Functional Assessment of Cancer Therapy Hepatobiliary Version 4 ( FACT-Hep v.4) (Quality of Life (QOL)) [Baseline through end of study up to 27.7 months]

   FACT-Hep consists of 45 items in five subscales (1) physical well-being (PWB) score rage 0 -28; (2) social well-being (SWB) score range 0-28; (3) emotional well-being (EWB) score range 0-24; (4) functional well-being (FWB) score range 0-28; and (5) the hepatobiliary cancer subscale (HCS) Score range 0-72. The Trial Outcomes Index (TOI) is the sum of the PWB, FWB and Hep subscales with a scores range of 0 to 128. The Total FACT-Hep score was the sum of all questions with a scores range of 0 to 180. The Total FACT-G score was the sum of the 27 questions in the PWB, SFWB, EWB and FWB with a scores range of 0 to 108. The FACT-Hep Symptoms Index with 8 key questions and scores range of 0 to 32 from the Hep Subscale. Higher score in sub-score or total score indicates better QOL and better health state. Participants were classified as "Improved" if they had positive change from baseline, "Worsened" if they had negative change from baseline, and "Stable" otherwise.

5. Relationship of Steady-State Drug Levels to Clinical Outcomes of Overall Survival (OS) [Randomization to date of death from any cause up to 27.7 months]

   OS was the duration from randomization to death from any cause. For participants who were alive at data cut-off, OS was censored at the last contact. Participants were categorized into 2 groups based on their steady state drug levels of Enzastaurin (total analyte=enzastaurin + LSN326020 [metabolite]): those participants below the median and those participants above the median [2786.042 nanomoles per /liter (nmol/l)]. The steady state drug levels and clinical outcomes were not evaluated for the Gemcitabine only treatment group.

6. Relationship of Steady-state Drug Levels to Best Overall Response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) (Disease Control) [Beginning of treatment up to 27.7 months]

   The overall disease control rate was calculated as percent of participants with overall response of complete response (CR), partial response (PR) or stable disease (SD) over number of per-protocol population. Using the Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria, CR: disappearance of all target and non-target lesions; PR: as at least a 30% decrease in sum of longest diameter (LD) of target lesions; progressive disease (PD) was defined as at least 20% increase in sum of LD of target lesions; SD: small changes that did not meet above criteria. Participants were categorized into 2 groups based on their steady state drug levels of Enzastaurin (total analyte=enzastaurin + LSN326020 [metabolite]): participants below the median and participants above the median [2754.521 nanomoles per liter (nmol/l)]. The steady state drug levels and clinical outcomes were not evaluated for the Gemcitabine only group.

7. Carbohydrate Antigen 19-9 (CA 19-9) Concentration in the Blood [Cycles 1 to 6, and post-treatment (up to 27.7 months)]

   CA19-9 is a tumor biomarker which was measured in the blood to assess the effect of treatment with enzastaurin.

8. Number of Participants Experiencing Serious Adverse Events (SAEs) and Adverse Events (AEs) (Toxicity) [Baseline through study completion (Up To 27.7 Months)]

   Clinically significant events were defined as SAEs and other non-serious adverse events (AEs). Participants who died due to progressive disease (PD), AEs while on treatment or died during the 30 day post-treatment are included. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of adenocarcinoma of the pancreas.

• Pretreatment tumor specimen must be available.

• No prior chemotherapy immunotherapy, biological therapy, or hormonal therapy for pancreatic cancer, including 5-fluorouracil (5-FU) with radiation therapy.

• Prior radiation allowed.

• Ability to stop some types of anti-seizure medicines within 14 days of enrollment.

Exclusion Criteria:

• Endocrine pancreatic tumor or ampullary cancer.

• Central Nervous System (CNS) metastases.

• Inability to swallow tablets.

• 10% or greater weight loss over the 6 weeks before study entry.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559), Mon - Fri, 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST) or speak with your personal physician	Dallas	Texas	United States

Sponsors and Collaborators

• Eli Lilly and Company

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Lilly Clinical Trial Registry

Publications

• Yount S, Cella D, Webster K, Heffernan N, Chang C, Odom L, van Gool R. Assessment of patient-reported clinical outcome in pancreatic and other hepatobiliary cancers: the FACT Hepatobiliary Symptom Index. J Pain Symptom Manage. 2002 Jul;24(1):32-44.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT00267020
• Other Study ID Numbers: 10463; H6Q-US-S002
• First Posted: Dec 20, 2005
• Last Update Posted: Aug 31, 2020
• Last Verified: Aug 1, 2020

• Additional relevant MeSH terms: Pancreatic Neoplasms; Gemcitabine

Study Results

Participant Flow

Pre-assignment Detail	Participant flow reports those participants who discontinued from study drug.

Arm/Group Title	Enzastaurin+Gemcitabine	Gemcitabine
Arm/Group Description	Enzastaurin: 1200 milligrams (mg) administered orally (as three 400-mg doses) after a meal on Day 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 2 to 28 in Cycle 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 1 to 28 in Cycle 2 and later. Gemcitabine: 1000 milligrams/square meter (mg/m^2) administered intravenously on Days 1, 8 and 15 of each 28-day cycle.	Gemcitabine: 1000 milligrams/square meter (mg/m^2) administered intravenously on Days 1, 8 and 15 of each 28-day cycle.
Period Title: Overall Study
STARTED	86	44
Received at Least 1 Dose	82	39
Per-Protocol Population	81	38
COMPLETED	0	1
NOT COMPLETED	86	43

Baseline Characteristics

Arm/Group Title	Enzastaurin+Gemcitabine	Gemcitabine	Total
Arm/Group Description	Enzastaurin: 1200 milligrams (mg) administered orally (as three 400-mg doses) after a meal on Day 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 2 to 28 in Cycle 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 1 to 28 in Cycle 2 and later. Gemcitabine: 1000 milligrams/square meter (mg/m^2) administered intravenously on Days 1, 8 and 15 of each 28-day cycle.	Gemcitabine: 1000 mg/m^2 administered intravenously on Days 1, 8 and 15 of each 28-day cycle.	Total of all reporting groups
Overall Participants	86	44	130
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	68.3	64.1	67.6
Sex: Female, Male (Count of Participants)
Female	40 46.5%	12 27.3%	52 40%
Male	46 53.5%	32 72.7%	78 60%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	9 10.5%	3 6.8%	12 9.2%
Not Hispanic or Latino	77 89.5%	41 93.2%	118 90.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	69 80.2%	35 79.5%	104 80%
Black or African American	7 8.1%	5 11.4%	12 9.2%
Asian	1 1.2%	1 2.3%	2 1.5%
Hispanic	9 10.5%	3 6.8%	12 9.2%
Region of Enrollment (Count of Participants)
United States	86 100%	44 100%	130 100%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
0 - Fully Active	36 41.9%	16 36.4%	52 40%
1 - Ambulatory, Restricted Strenuous Activity	43 50%	25 56.8%	68 52.3%
2 - Ambulatory, No Work Activities	7 8.1%	3 6.8%	10 7.7%
Body Surface Area (BSA) (square meter (m^2)) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [square meter (m^2)]	1.8 (0.24)	1.9 (0.21)	1.8 (0.23)
Diagnosis Stage (Count of Participants)
Stage IIA	3 3.5%	0 0%	3 2.3%
Stage IIB	4 4.7%	2 4.5%	6 4.6%
Stage III	7 8.1%	7 15.9%	14 10.8%
Stage IV	72 83.7%	35 79.5%	107 82.3%
Current Stage (Count of Participants)
Stage IIB	1 1.2%	1 2.3%	2 1.5%
Stage III	7 8.1%	5 11.4%	12 9.2%
Stage IV	78 90.7%	38 86.4%	116 89.2%

Outcome Measures

1. Primary Outcome

Title	Overall Survival (OS)
Description	OS was the duration from randomization to death. OS was censored at the last contact for participants who were alive, at the cut-off date.
Time Frame	Randomization to the date of death from any cause up to 27.7 months

Outcome Measure Data

Analysis Population Description

Intent-to -treat (ITT) population: All randomized participants. Participants censored: Enzastaurin+Gemcitabine = 17; Gemcitabine = 11.

Arm/Group Title	Enzastaurin+Gemcitabine	Gemcitabine
Arm/Group Description	Enzastaurin: 1200 milligrams (mg) administered orally (as three 400-mg doses) after a meal on Day 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 2 to 28 in Cycle 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 1 to 28 in Cycle 2 and later. Gemcitabine: 1000 milligrams/square meter (mg/m^2) administered intravenously on Days 1, 8 and 15 of each 28-day cycle.	Gemcitabine: 1000 mg/m^2 administered intravenously on Days 1, 8 and 15 of each 28-day cycle.
Measure Participants	86	44
Median (95% Confidence Interval) [months]	5.6	5.1

2. Secondary Outcome

Title	Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Response Rate)
Description	Response rate was defined as percentage of responders (best study response recorded as CR or PR) from the qualified number of participants for tumor response analysis. Response defined using Response Evaluation Criteria In Solid Tumors (RECIST, v1.0) criteria: CR was disappearance of all target lesions for at least 4 weeks. PR was at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of LD. Percentage of participants was calculated as: (The number of responders with CR or PR/ The number of participants qualified for tumor response analysis) × 100.
Time Frame	Randomization to measured progressive disease (PD) up to 19.9 months

Outcome Measure Data

Analysis Population Description

Per Protocol Population: Randomized participants who had: 1) histological or cytological diagnosis of locally advanced (Stage II, III) or metastatic (Stage IV) adenocarcinoma of the pancreas; 2) no concurrent systemic chemotherapy; 3) presence of measurable disease at baseline; and 4) received at least 1 dose of study drug.

Arm/Group Title	Enzastaurin+Gemcitabine	Gemcitabine
Arm/Group Description	Enzastaurin: 1200 milligrams (mg) administered orally (as three 400-mg doses) after a meal on Day 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 2 to 28 in Cycle 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 1 to 28 in Cycle 2 and later. Gemcitabine: 1000 milligrams/square meter (mg/m^2) administered intravenously on Days 1, 8 and 15 of each 28-day cycle.	Gemcitabine: 1000 mg/m^2 administered intravenously on Days 1, 8 and 15 of each 28-day cycle.
Measure Participants	81	38
CR	1.2 1.4%	0 0%
PR	7.4 8.6%	5.3 12%

3. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was defined as the time from the date of randomization to the first date of documented progressive disease (PD) or death due to any cause, whichever occurred first. PFS was censored at the date of the last assessment visit for participants who were still alive at data cut-off and who had not had documented progressive disease. Participants who started a new treatment before progression were censored as of the date of the start of new treatment.
Time Frame	Randomization to measured PD or death from any cause up to 21.6 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population: All randomized participants. Participants censored: Enzastaurin+Gemcitabine = 21; Gemcitabine = 10.

Arm/Group Title	Enzastaurin+Gemcitabine	Gemcitabine
Arm/Group Description	Enzastaurin: 1200 milligrams (mg) administered orally (as three 400-mg doses) after a meal on Day 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 2 to 28 in Cycle 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 1 to 28 in Cycle 2 and later. Gemcitabine: 1000 milligrams/square meter (mg/m^2) administered intravenously on Days 1, 8 and 15 of each 28-day cycle.	Gemcitabine: 1000 mg/m^2 administered intravenously on Days 1, 8 and 15 of each 28-day cycle.
Measure Participants	86	44
Median (95% Confidence Interval) [months]	3.4	3.0

4. Secondary Outcome

Title	Duration of Response
Description	The duration of a complete response (CR) or partial response (PR) was defined, using the Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria, as the time from first objective status assessment of CR or PR to the first time of disease progression or death as a result of any cause. Using the Response Evaluation Criteria in Solid Tumors (RECIST V1.0) criteria, CR was defined as the disappearance of all tumor lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum of LD. Duration of response was censored at the date of the last assessment visit for responders who were still alive at data cut-off and had no documented progressive disease (PD).
Time Frame	Time of response to PD or death from any cause up to 19.9 months

Outcome Measure Data

Analysis Population Description

Participants in the Per Protocol population with a CR or PR: With histological or cytological diagnosis of locally advanced adenocarcinoma of the pancreas; no concurrent systemic chemotherapy; presence of measurable disease at baseline; and treatment with at least 1 dose of study drug. Censored: Enzastaurin+Gemcitabine = 1; Gemcitabine = 0.

Arm/Group Title	Enzastaurin+Gemcitabine	Gemcitabine
Arm/Group Description	Enzastaurin: 1200 milligrams (mg) administered orally (as three 400-mg doses) after a meal on Day 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 2 to 28 in Cycle 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 1 to 28 in Cycle 2 and later. Gemcitabine: 1000 milligrams/square meter (mg/m^2) administered intravenously on Days 1, 8 and 15 of each 28-day cycle.	Gemcitabine: 1000 mg/m^2 administered intravenously on Days 1, 8 and 15 of each 28-day cycle.
Measure Participants	7	2
Median (95% Confidence Interval) [months]	4.6	9.2

5. Secondary Outcome

Title	Change in Scores From Baseline (Improved, Stable or Worsened) to End of Study in Functional Assessment of Cancer Therapy Hepatobiliary Version 4 ( FACT-Hep v.4) (Quality of Life (QOL))
Description	FACT-Hep consists of 45 items in five subscales (1) physical well-being (PWB) score rage 0 -28; (2) social well-being (SWB) score range 0-28; (3) emotional well-being (EWB) score range 0-24; (4) functional well-being (FWB) score range 0-28; and (5) the hepatobiliary cancer subscale (HCS) Score range 0-72. The Trial Outcomes Index (TOI) is the sum of the PWB, FWB and Hep subscales with a scores range of 0 to 128. The Total FACT-Hep score was the sum of all questions with a scores range of 0 to 180. The Total FACT-G score was the sum of the 27 questions in the PWB, SFWB, EWB and FWB with a scores range of 0 to 108. The FACT-Hep Symptoms Index with 8 key questions and scores range of 0 to 32 from the Hep Subscale. Higher score in sub-score or total score indicates better QOL and better health state. Participants were classified as "Improved" if they had positive change from baseline, "Worsened" if they had negative change from baseline, and "Stable" otherwise.
Time Frame	Baseline through end of study up to 27.7 months

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least one dose of study drug and had data for FACT-Hep questionnaire.

Arm/Group Title	Enzastaurin+Gemcitabine	Gemcitabine
Arm/Group Description	Enzastaurin: 1200 milligrams (mg) administered orally (as three 400-mg doses) after a meal on Day 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 2 to 28 in Cycle 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 1 to 28 in Cycle 2 and later. Gemcitabine: 1000 milligrams/square meter (mg/m^2) administered intravenously on Days 1, 8 and 15 of each 28-day cycle.	Gemcitabine: 1000 mg/m^2 administered intravenously on Days 1, 8 and 15 of each 28-day cycle.
Measure Participants	33	17
Physical well-being- Improved	7.2 (3.48)	6.5 (2.71)
Physical well-being- Stable	0.3 (1.16)	0.8 (1.80)
Physical well-being- Worsened	-10.0 (4.08)	-7.8 (3.96)
Social well-being- Improved	3.8 (0.64)	4.7 (2.10)
Social well-being- Stable	0.1 (1.06)	-0.6 (1.21)
Social well-being- Worsened	-6.5 (3.80)	-5.5 (2.66)
Emotional well-being- Improved	6.9 (4.76)	6.7 (3.79)
Emotional well-being- Stable	0 (1.29)	-0.1 (1.36)
Emotional well-being- Worsened	-5.8 (2.57)	-8.2 (4.15)
Functional well-being- Improved	6.8 (3.63)	6.5 (1.73)
Functional well-being- Stable	-0.2 (1.40)	-1.1 (0.90)
Functional well-being- Worsened	-10.6 (5.37)	-8.5 (4.42)
Hepatobiliary cancer subscale- Improved	12.7 (4.67)	12.0 (5.20)
Hepatobiliary cancer subscale- Stable	0.5 (3.00)	0.7 (3.78)
Hepatobiliary cancer subscale- Worsened	-14.6 (4.70)	-10.0 (4.32)
Total Outcome Index- Improved	21.4 (11.20)	19.0 (11.49)
Total outcome index- Stable	-1.6 (5.40)	-1.3 (4.76)
Total outcome index- Worsened	-35.9 (13.03)	-23.0 (9.88)
Total FACT-Hep score- Improved	30.0 (16.81)	27.5 (17.91)
Total FACT-Hep score- Stable	-1.2 (5.65)	0 (4.19)
Total FACT-Hep score- Worsened	-37.9 (13.71)	-26.6 (12.26)
Total FACT-G-score- Improved	19.1 (11.63)	24.1 (18.95)
Total FACT-G-score- Stable	-0.5 (3.56)	-0.6 (4.17)
Total FACT-G-score- Worsened	-20.1 (10.59)	-21.2 (10.75)
FACT Hep Symptoms Index- Improved	7.4 (3.95)	6.3 (2.50)
FACT Hep Symptoms Index- Stable	0.5 (1.45)	0.1 (1.85)
FACT Hep Symptoms Index- Worsened	-7.0 (3.31)	-7.0 (2.16)

6. Secondary Outcome

Title	Relationship of Steady-State Drug Levels to Clinical Outcomes of Overall Survival (OS)
Description	OS was the duration from randomization to death from any cause. For participants who were alive at data cut-off, OS was censored at the last contact. Participants were categorized into 2 groups based on their steady state drug levels of Enzastaurin (total analyte=enzastaurin + LSN326020 [metabolite]): those participants below the median and those participants above the median [2786.042 nanomoles per /liter (nmol/l)]. The steady state drug levels and clinical outcomes were not evaluated for the Gemcitabine only treatment group.
Time Frame	Randomization to date of death from any cause up to 27.7 months

Outcome Measure Data

Analysis Population Description

All participants who received at least 1 dose of study drug. Participants censored: Below median = 4; Above median =4.

Arm/Group Title	Enzastaurin+Gemcitabine
Arm/Group Description	Enzastaurin: 1200 milligrams (mg) administered orally (as three 400-mg doses) after a meal on Day 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 2 to 28 in Cycle 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 1 to 28 in Cycle 2 and later. Gemcitabine: 1000 milligrams/square meter (mg/m^2) administered intravenously on Days 1, 8 and 15 of each 28-day cycle.
Measure Participants	57
Below median	7.2
Above median	5.6

7. Secondary Outcome

Title	Relationship of Steady-state Drug Levels to Best Overall Response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) (Disease Control)
Description	The overall disease control rate was calculated as percent of participants with overall response of complete response (CR), partial response (PR) or stable disease (SD) over number of per-protocol population. Using the Response Evaluation Criteria in Solid Tumors (RECIST v1.0) criteria, CR: disappearance of all target and non-target lesions; PR: as at least a 30% decrease in sum of longest diameter (LD) of target lesions; progressive disease (PD) was defined as at least 20% increase in sum of LD of target lesions; SD: small changes that did not meet above criteria. Participants were categorized into 2 groups based on their steady state drug levels of Enzastaurin (total analyte=enzastaurin + LSN326020 [metabolite]): participants below the median and participants above the median [2754.521 nanomoles per liter (nmol/l)]. The steady state drug levels and clinical outcomes were not evaluated for the Gemcitabine only group.
Time Frame	Beginning of treatment up to 27.7 months

Outcome Measure Data

Analysis Population Description

Randomized participants who had: 1) Histological or cytological diagnosis of locally advanced (Stage II, III) or metastatic (Stage IV) adenocarcinoma of the pancreas; 2) no concurrent systemic chemotherapy; 3) presence of measurable disease at baseline; and 4) received at least 1 dose of study drug and had data for overall response.

Arm/Group Title	Enzastaurin+Gemcitabine
Arm/Group Description	Enzastaurin: 1200 milligrams (mg) administered orally (as three 400-mg doses) after a meal on Day 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 2 to 28 in Cycle 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 1 to 28 in Cycle 2 and later. Gemcitabine: 1000 milligrams/square meter (mg/m^2) administered intravenously on Days 1, 8 and 15 of each 28-day cycle.
Measure Participants	28
CR (Below median)	3.6 4.2%
CR (Above median)	0.0 0%
PR (Below median)	17.9 20.8%
PR (Above median)	3.6 4.2%
SD (Below median)	57.1 66.4%
SD (Above median)	39.3 45.7%
PD (Below median)	14.3 16.6%
PD (Above median)	32.1 37.3%
Disease Control (Below median)	78.6 91.4%
Disease Control (Above median)	42.9 49.9%

8. Secondary Outcome

Title	Carbohydrate Antigen 19-9 (CA 19-9) Concentration in the Blood
Description	CA19-9 is a tumor biomarker which was measured in the blood to assess the effect of treatment with enzastaurin.
Time Frame	Cycles 1 to 6, and post-treatment (up to 27.7 months)

Outcome Measure Data

Analysis Population Description

Safety population: All randomized participants who received at least 1 dose of study drug.

Arm/Group Title	Enzastaurin+Gemcitabine	Gemcitabine
Arm/Group Description	Enzastaurin: 1200 milligrams (mg) administered orally (as three 400-mg doses) after a meal on Day 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 2 to 28 in Cycle 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 1 to 28 in Cycle 2 and later. Gemcitabine: 1000 milligrams/square meter (mg/m^2) administered intravenously on Days 1, 8 and 15 of each 28-day cycle.	Gemcitabine: 1000 mg/m^2 administered intravenously on Days 1, 8 and 15 of each 28-day cycle.
Measure Participants	82	39
Cycle 1	31708.5 (134178.00)	12038.6 (26659.50)
Cycle 2	12828.4 (33051.54)	40764.9 (143995.67)
Cycle 3	24709.5 (114098.20)	1573.0 (2811.74)
Cycle 4	37261.0 (168939.81)	1102.7 (1547.67)
Cycle 5	392.3 (744.91)	403.1 (541.91)
Cycle 6	600.9 (1268.90)	938.5 (1542.34)
Post-treatment 1st visit	19420.5 (45867.95)	11351.3 (23890.66)
Post-treatment 2nd visit	19557.7 (32615.58)	93955.9 (176684.42)

9. Secondary Outcome

Title	Number of Participants Experiencing Serious Adverse Events (SAEs) and Adverse Events (AEs) (Toxicity)
Description	Clinically significant events were defined as SAEs and other non-serious adverse events (AEs). Participants who died due to progressive disease (PD), AEs while on treatment or died during the 30 day post-treatment are included. A summary of SAEs and other non-serious AEs regardless of causality is located in the Reported Adverse Events module.
Time Frame	Baseline through study completion (Up To 27.7 Months)

Outcome Measure Data

Analysis Population Description

Safety population: All participants who received at least 1 dose of study drug.

Arm/Group Title	Enzastaurin+Gemcitabine	Gemcitabine
Arm/Group Description	Enzastaurin: 1200 milligrams (mg) administered orally (as three 400-mg doses) after a meal on Day 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 2 to 28 in Cycle 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 1 to 28 in Cycle 2 and later. Gemcitabine: 1000 milligrams/square meter (mg/m^2) administered intravenously on Days 1, 8 and 15 of each 28-day cycle.	Gemcitabine: 1000 mg/m^2 administered intravenously on Days 1, 8 and 15 of each 28-day cycle.
Measure Participants	82	39
Non-serious AEs	80 93%	38 86.4%
SAEs	49 57%	23 52.3%
Deaths due to PD	3 3.5%	1 2.3%
Deaths due to AEs	4 4.7%	1 2.3%
Deaths within 30-days after treatment	3 3.5%	1 2.3%

Adverse Events

Time Frame	Baseline through study completion (27.7 months)
Adverse Event Reporting Description	Study-specific clinical outcomes due to progressive disease were not considered to be serious adverse events (SAEs) unless it was deemed related to study drug by the investigator.
Arm/Group Title	Enzastaurin+Gemcitabine		Gemcitabine
Arm/Group Description	Enzastaurin: 1200 milligrams (mg) administered orally (as three 400-mg doses) after a meal on Day 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 2 to 28 in Cycle 1, then 500 mg orally, daily (as five 100-mg tablets) after lunch on Days 1 to 28 in Cycle 2 and later. Gemcitabine: 1000 milligrams/square meter (mg/m^2) administered intravenously on Days 1, 8 and 15 of each 28-day cycle.		Gemcitabine: 1000 mg/m^2 administered intravenously on Days 1, 8 and 15 of each of each 28-day cycle.
All Cause Mortality
	Enzastaurin+Gemcitabine		Gemcitabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Enzastaurin+Gemcitabine		Gemcitabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/82 (59.8%)		23/39 (59%)
Blood and lymphatic system disorders
Anaemia	4/82 (4.9%)	4	1/39 (2.6%)	1
Thrombocytopenia	1/82 (1.2%)	1	1/39 (2.6%)	1
Cardiac disorders
Acute myocardial infarction	0/82 (0%)	0	1/39 (2.6%)	1
Atrial fibrillation	1/82 (1.2%)	1	0/39 (0%)	0
Atrial flutter	0/82 (0%)	0	1/39 (2.6%)	1
Cardiac arrest	1/82 (1.2%)	1	0/39 (0%)	0
Myocardial infarction	1/82 (1.2%)	1	0/39 (0%)	0
Gastrointestinal disorders
Abdominal pain	4/82 (4.9%)	4	0/39 (0%)	0
Abdominal pain upper	1/82 (1.2%)	1	0/39 (0%)	0
Ascites	1/82 (1.2%)	1	0/39 (0%)	0
Constipation	1/82 (1.2%)	1	1/39 (2.6%)	1
Diarrhoea	4/82 (4.9%)	4	0/39 (0%)	0
Gastrointestinal haemorrhage	2/82 (2.4%)	2	0/39 (0%)	0
Ileus	1/82 (1.2%)	1	1/39 (2.6%)	1
Intestinal obstruction	1/82 (1.2%)	1	0/39 (0%)	0
Intestinal perforation	2/82 (2.4%)	2	0/39 (0%)	0
Nausea	5/82 (6.1%)	5	0/39 (0%)	0
Oesophageal varices haemorrhage	1/82 (1.2%)	1	0/39 (0%)	0
Pancreatitis	1/82 (1.2%)	1	0/39 (0%)	0
Pancreatitis acute	1/82 (1.2%)	1	0/39 (0%)	0
Small intestinal obstruction	1/82 (1.2%)	1	0/39 (0%)	0
Vomiting	4/82 (4.9%)	4	0/39 (0%)	0
General disorders
Asthenia	1/82 (1.2%)	1	0/39 (0%)	0
Chest pain	2/82 (2.4%)	2	0/39 (0%)	0
Disease progression	1/82 (1.2%)	1	1/39 (2.6%)	1
Gait disturbance	1/82 (1.2%)	1	1/39 (2.6%)	1
Oedema peripheral	0/82 (0%)	0	1/39 (2.6%)	1
Pain	2/82 (2.4%)	2	3/39 (7.7%)	3
Thrombosis in device	1/82 (1.2%)	1	0/39 (0%)	0
Hepatobiliary disorders
Bile duct obstruction	1/82 (1.2%)	1	0/39 (0%)	0
Bile duct stenosis	0/82 (0%)	0	1/39 (2.6%)	1
Cholangitis	2/82 (2.4%)	2	1/39 (2.6%)	1
Hyperbilirubinaemia	1/82 (1.2%)	1	0/39 (0%)	0
Jaundice	1/82 (1.2%)	1	0/39 (0%)	0
Jaundice cholestatic	0/82 (0%)	0	1/39 (2.6%)	1
Infections and infestations
Bacteraemia	2/82 (2.4%)	2	1/39 (2.6%)	1
Bacterial sepsis	0/82 (0%)	0	1/39 (2.6%)	1
Cellulitis	1/82 (1.2%)	1	1/39 (2.6%)	1
Device related infection	1/82 (1.2%)	1	0/39 (0%)	0
Escherichia sepsis	1/82 (1.2%)	1	0/39 (0%)	0
Infection	1/82 (1.2%)	1	0/39 (0%)	0
Peritonitis	0/82 (0%)	0	1/39 (2.6%)	1
Pneumonia	1/82 (1.2%)	1	1/39 (2.6%)	1
Sepsis	2/82 (2.4%)	2	0/39 (0%)	0
Urinary tract infection	1/82 (1.2%)	1	0/39 (0%)	0
Urosepsis	1/82 (1.2%)	1	0/39 (0%)	0
Investigations
Blood bilirubin increased	0/82 (0%)	0	1/39 (2.6%)	1
Weight decreased	1/82 (1.2%)	1	0/39 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	1/82 (1.2%)	1	0/39 (0%)	0
Dehydration	7/82 (8.5%)	7	3/39 (7.7%)	3
Failure to thrive	1/82 (1.2%)	1	0/39 (0%)	0
Hyperglycaemia	1/82 (1.2%)	1	2/39 (5.1%)	2
Hyponatraemia	0/82 (0%)	0	1/39 (2.6%)	1
Hypovolaemia	0/82 (0%)	0	1/39 (2.6%)	1
Musculoskeletal and connective tissue disorders
Back pain	0/82 (0%)	0	1/39 (2.6%)	1
Muscular weakness	0/82 (0%)	0	1/39 (2.6%)	1
Nervous system disorders
Cerebrovascular accident	2/82 (2.4%)	2	1/39 (2.6%)	1
Dizziness	1/82 (1.2%)	1	0/39 (0%)	0
Encephalopathy	0/82 (0%)	0	1/39 (2.6%)	1
Syncope	2/82 (2.4%)	2	1/39 (2.6%)	1
Thrombotic stroke	1/82 (1.2%)	1	0/39 (0%)	0
Psychiatric disorders
Confusional state	1/82 (1.2%)	1	0/39 (0%)	0
Depression	1/82 (1.2%)	1	0/39 (0%)	0
Hallucination	1/82 (1.2%)	1	0/39 (0%)	0
Renal and urinary disorders
Renal failure	1/82 (1.2%)	1	0/39 (0%)	0
Renal failure acute	1/82 (1.2%)	1	0/39 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/82 (1.2%)	1	0/39 (0%)	0
Dyspnoea	1/82 (1.2%)	1	0/39 (0%)	0
Hydropneumothorax	1/82 (1.2%)	1	0/39 (0%)	0
Pleural effusion	1/82 (1.2%)	1	1/39 (2.6%)	1
Pneumothorax	1/82 (1.2%)	1	0/39 (0%)	0
Pulmonary embolism	7/82 (8.5%)	7	2/39 (5.1%)	2
Surgical and medical procedures
Internal fixation of fracture	1/82 (1.2%)	1	0/39 (0%)	0
Vascular disorders
Arteriosclerosis	1/82 (1.2%)	1	0/39 (0%)	0
Deep vein thrombosis	5/82 (6.1%)	5	5/39 (12.8%)	5
Venous thrombosis	1/82 (1.2%)	1	0/39 (0%)	0
Other (Not Including Serious) Adverse Events
	Enzastaurin+Gemcitabine		Gemcitabine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	80/82 (97.6%)		38/39 (97.4%)
Blood and lymphatic system disorders
Leukopenia	26/82 (31.7%)	26	14/39 (35.9%)	14
Lymphopenia	3/82 (3.7%)	3	3/39 (7.7%)	3
Eye disorders
Vision blurred	2/82 (2.4%)	2	2/39 (5.1%)	3
Gastrointestinal disorders
Abdominal distension	5/82 (6.1%)	5	1/39 (2.6%)	1
Abdominal pain	26/82 (31.7%)	26	8/39 (20.5%)	9
Ascites	1/82 (1.2%)	1	2/39 (5.1%)	2
Constipation	24/82 (29.3%)	24	11/39 (28.2%)	11
Diarrhoea	25/82 (30.5%)	25	10/39 (25.6%)	10
Dyspepsia	4/82 (4.9%)	4	2/39 (5.1%)	2
Gastrointestinal haemorrhage	2/82 (2.4%)	2	2/39 (5.1%)	2
Haemorrhoids	1/82 (1.2%)	1	2/39 (5.1%)	2
Nausea	35/82 (42.7%)	35	13/39 (33.3%)	13
Oesophagitis	5/82 (6.1%)	5	2/39 (5.1%)	2
Vomiting	17/82 (20.7%)	17	7/39 (17.9%)	7
General disorders
Chills	4/82 (4.9%)	4	2/39 (5.1%)	2
Fatigue	50/82 (61%)	50	22/39 (56.4%)	22
Oedema	10/82 (12.2%)	10	1/39 (2.6%)	1
Oedema peripheral	25/82 (30.5%)	25	12/39 (30.8%)	12
Pain	5/82 (6.1%)	5	3/39 (7.7%)	3
Pyrexia	15/82 (18.3%)	15	6/39 (15.4%)	6
Hepatobiliary disorders
Hyperbilirubinaemia	7/82 (8.5%)	7	3/39 (7.7%)	3
Immune system disorders
Hypersensitivity	2/82 (2.4%)	2	3/39 (7.7%)	3
Infections and infestations
Pneumonia	1/82 (1.2%)	1	3/39 (7.7%)	3
Skin infection	4/82 (4.9%)	4	2/39 (5.1%)	2
Injury, poisoning and procedural complications
Vascular access complication	5/82 (6.1%)	5	2/39 (5.1%)	2
Investigations
Alanine aminotransferase increased	2/82 (2.4%)	2	7/39 (17.9%)	7
Aspartate aminotransferase increased	4/82 (4.9%)	4	6/39 (15.4%)	6
Blood alkaline phosphatase increased	10/82 (12.2%)	10	6/39 (15.4%)	6
Blood creatinine increased	5/82 (6.1%)	5	1/39 (2.6%)	1
Haemoglobin decreased	46/82 (56.1%)	46	23/39 (59%)	23
Laboratory test abnormal	5/82 (6.1%)	5	1/39 (2.6%)	1
Neutrophil count decreased	32/82 (39%)	32	18/39 (46.2%)	18
Platelet count decreased	46/82 (56.1%)	46	20/39 (51.3%)	20
Weight decreased	9/82 (11%)	9	6/39 (15.4%)	6
Weight increased	3/82 (3.7%)	3	2/39 (5.1%)	2
Metabolism and nutrition disorders
Decreased appetite	23/82 (28%)	23	16/39 (41%)	16
Dehydration	9/82 (11%)	9	3/39 (7.7%)	3
Hyperglycaemia	5/82 (6.1%)	5	5/39 (12.8%)	5
Hyperkalaemia	5/82 (6.1%)	5	0/39 (0%)	0
Hypoalbuminaemia	7/82 (8.5%)	7	4/39 (10.3%)	4
Hypocalcaemia	3/82 (3.7%)	3	2/39 (5.1%)	2
Hypokalaemia	7/82 (8.5%)	7	4/39 (10.3%)	4
Hyponatraemia	9/82 (11%)	9	3/39 (7.7%)	3
Musculoskeletal and connective tissue disorders
Arthralgia	4/82 (4.9%)	4	2/39 (5.1%)	2
Back pain	9/82 (11%)	10	5/39 (12.8%)	5
Bone pain	3/82 (3.7%)	3	2/39 (5.1%)	2
Muscular weakness	10/82 (12.2%)	10	9/39 (23.1%)	9
Myalgia	3/82 (3.7%)	3	3/39 (7.7%)	3
Pain in extremity	6/82 (7.3%)	7	4/39 (10.3%)	4
Nervous system disorders
Ataxia	2/82 (2.4%)	2	2/39 (5.1%)	2
Dizziness	10/82 (12.2%)	10	4/39 (10.3%)	4
Dysgeusia	1/82 (1.2%)	1	3/39 (7.7%)	3
Headache	6/82 (7.3%)	6	1/39 (2.6%)	1
Peripheral sensory neuropathy	6/82 (7.3%)	6	3/39 (7.7%)	3
Speech disorder	0/82 (0%)	0	2/39 (5.1%)	2
Tremor	0/82 (0%)	0	2/39 (5.1%)	2
Psychiatric disorders
Anxiety	6/82 (7.3%)	6	3/39 (7.7%)	3
Depressed mood	8/82 (9.8%)	8	2/39 (5.1%)	2
Insomnia	12/82 (14.6%)	12	2/39 (5.1%)	2
Renal and urinary disorders
Chromaturia	10/82 (12.2%)	10	1/39 (2.6%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	17/82 (20.7%)	17	7/39 (17.9%)	7
Epistaxis	2/82 (2.4%)	2	2/39 (5.1%)	2
Hiccups	1/82 (1.2%)	1	2/39 (5.1%)	2
Rhinitis allergic	1/82 (1.2%)	1	2/39 (5.1%)	2
Skin and subcutaneous tissue disorders
Hyperhidrosis	5/82 (6.1%)	5	1/39 (2.6%)	1
Pruritus	3/82 (3.7%)	3	2/39 (5.1%)	2
Rash erythematous	4/82 (4.9%)	4	2/39 (5.1%)	2
Vascular disorders
Haematoma	6/82 (7.3%)	6	2/39 (5.1%)	2
Hypertension	1/82 (1.2%)	1	2/39 (5.1%)	2
Hypotension	7/82 (8.5%)	7	3/39 (7.7%)	3
Thrombosis	1/82 (1.2%)	1	2/39 (5.1%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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