Enzastaurin in Combination of Capecitabine to Treat Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine whether the combination of enzastaurin and capecitabine is more effective than the combination of placebo and capecitabine in treating participants with breast cancer who were previously treated with an anthracycline and a taxane.

Official Title
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A Double-Blind, Randomized, Phase 2 Trial of Capecitabine Plus Enzastaurin Versus Capecitabine Plus Placebo in Patients With Metastatic or Recurrent Breast Cancer Previously Treated With an Anthracycline and a Taxane

Conditions
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Breast Cancer

Intervention / Treatment
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* Drug: enzastaurin
* Drug: placebo
* Drug: capecitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have been diagnosed with metastatic or recurrent breast cancer. Have been previously treated with both an anthracycline and a taxane. Have not received more than two prior chemotherapy treatment programs. Have stopped any antitumoral hormonal treatment before you enroll in this study. Have a negative pregnancy blood test if menstruating or capable of becoming pregnant. You must use an approved birth control method during the study and for 3 months after stopping study treatment. Exclusion Criteria: Cannot follow the study procedures (for example, you cannot swallow tablets). Are receiving another treatment for your cancer. Have received another experimental drug in the last 4 weeks. Have had serious heart disease within last 6 months. Are pregnant or breast-feeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Capecitabine + Enzastaurin<br> | Drug: enzastaurin<br>* 1125 milligrams (mg) loading dose then 500 mg, oral, daily, 21-day cycles until progressive disease<br>* Other names: LY317615;Drug: capecitabine<br>* 1250 mg/m^2, BID, days 1-14 of each 21-day cycle until progressive disease<br>|
| Placebo Comparator: Capecitabine + Placebo<br> | Drug: placebo<br>* oral, daily, 21-day cycles until progressive disease<br>Drug: capecitabine<br>* 1250 mg/m^2, BID, days 1-14 of each 21-day cycle until progressive disease<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS was defined as the time from randomization to the first observation of disease progression or death due to any cause. For participants not known to have died as of the data cut-off date and who did not have progressive disease, PFS was censored at the date of last visit with adequate assessment. For participants who received subsequent anticancer therapy (after discontinuation from the study treatment) prior to disease progression or death, PFS was censored at the date of last visit with adequate assessment prior to the initiation of post-discontinuation anticancer therapy. | Randomization to measured progressive disease or death up to 14 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expression of Tumor Markers in Tissue Samples (Tumor Markers and Genes Evaluation) | Protein expression was planned to be measured using an Immunohistochemistry (IHC) assay to determine membrane and cytoplasmic phosphorylated glycogen synthase kinase 3 beta (pGSK3B), nuclear phosphorylated adenosine 3'5'-cyclic monophosphate (cAMP) response-element binding protein (pCREB), cytoplasmic pCREB, protein kinase C beta 2 (PKCB2), cytoplasmic phospho S6 (pS6), and cytoplasmic phosphatase and tensin homolog (PTEN) IHC H-scores. Tumor tissue samples were to be scored using a 0 (negative, no staining) to 3+ (brightest staining) scoring system for cytoplasmic and nuclear staining, and H- scores calculated using formula: 1x(percentage of cells stained 1+) + 2x(percentage of cells stained 2+) + 3x(percentage of cells stained 3+) . | Randomization, Cycle 2, end of study | 
| Pharmacokinetics: Area Under the Concentration Versus Time Curve During One Dosing Interval at Steady State | Area Under the Concentration versus time curve during 1 dosing interval at steady state (AUCτ,ss) for Cycle 2 Day 1 for Enzastaurin, its metabolite LY326020 and total analytes (enzastaurin + LY326020). AUCτ,ss was calculated using concentration versus time data by post hoc estimation of enzastaurin, its metabolite LY326020, and total analytes (enzastaurin + LY326020). | From pre-dose to 24 hours post-dose on Day 1 of Cycle 2 | 
| Pharmacokinetics: Area Under the Concentration Curve Versus Time From Time 0 to Last Quantifiable Value (AUC0-tlast) of Capecitabine | AUC0-tlast for Capecitabine, 5'-deoxy-5-fluorouridine (5'-DFUR) and 5-fluorouracil (5-FU) was calculated from the plasma concentration-time data for each analyte for Cycle 2, Day 1. | Pre-dose to 6 hours post-dose on Day 1 of Cycle 2 | 
| Pharmacokinetics: Maximum Observed Concentration (Cmax) of Capecitabine | Cmax for Capecitabine, 5'-deoxy-5-fluorouridine (5'-DFUR) and its metabolites 5-fluorouracil (5-FU) was calculated from the plasma concentration-time data for each analyte for Day 1 of Cycle 2. | From pre-dose to 6 hours post-dose on Day 1 of Cycle 2 | 
| Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate) | Response rate was defined as percent of participants with objective response [CR or PR] over randomized and treated participants using the Response Evaluation Criteria in Solid Tumors (RECIST v1.0) Guidelines. 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 LDs or complete disappearance of target lesions, with persistence (but not worsening) of one or more non-target lesions. No new lesions may have appeared. | Randomization to last visit (up to 9.66 months) | 
| Duration of Response (DOR) | The DOR was defined as the time from first objective status assessment of complete response (CR) or partial response (PR) to the first time of progression or death as a result of any cause. According to the Response Evaluation Criteria in Solid Tumors (RECIST V1.0) criteria, CR was the disappearance of all tumor lesions. PR was at least a 30% decrease in the sum of the longest diameter (LD) of target lesions or complete disappearance of target lesions, with persistence (but not worsening) of 1 or more non-target lesions, with occurrence of no new lesions. For participants not known to have died as of the data cut-off date and who did not have progressive disease, DOR was censored at the date of last visit with adequate assessment. For participants who received subsequent anticancer therapy (after discontinuation from the study treatment) prior to disease progression or death, DOR was censored at the date of last visit with adequate assessment. | Randomization to last visit (up to 9.66 months) | 
| Overall Survival (OS) | OS was defined as the time in months from the date of study enrollment to the date of death from any cause. For participants not known to have died as of the cut-off date, OS was censored at the last contact date. | Randomization to date of death from any cause up to 20.83 months | 
| Pharmacology Toxicity and Adverse Events (AEs) | Data presented are the number of participants who experienced serious AEs, AEs, death due to progressive disease (PD), death due to AEs while on treatment and death during the 30-day post-treatment. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. | Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up] |