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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Pancreatic Neoplasm

Intervention / Treatment
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* Drug: enzastaurin
* Drug: gemcitabine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | 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. | Randomization to the date of death from any cause up to 27.7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Response Rate) | 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. | Randomization to measured progressive disease (PD) up to 19.9 months | 
| Progression Free Survival (PFS) | 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. | Randomization to measured PD or death from any cause up to 21.6 months | 
| Duration of Response | 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 of response to PD or death from any cause up to 19.9 months | 
| 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)) | 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. | Baseline through end of study up to 27.7 months | 
| Relationship of Steady-State Drug Levels to Clinical Outcomes of Overall Survival (OS) | 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. | Randomization to date of death from any cause up to 27.7 months | 
| Relationship of Steady-state Drug Levels to Best Overall Response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) (Disease Control) | 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. | Beginning of treatment up to 27.7 months | 
| Carbohydrate Antigen 19-9 (CA 19-9) Concentration in the Blood | CA19-9 is a tumor biomarker which was measured in the blood to assess the effect of treatment with enzastaurin. | Cycles 1 to 6, and post-treatment (up to 27.7 months) | 
| Number of Participants Experiencing Serious Adverse Events (SAEs) and Adverse Events (AEs) (Toxicity) | 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. | Baseline through study completion (Up To 27.7 Months) |