Enzastaurin in Combination of Capecitabine to Treat Breast Cancer

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.

Time frame: Randomization to measured progressive disease or death up to 14 months

Population: Intent-to-treat (ITT) population: All randomized participants who received at least 1 dose of study drug.~Participants censored: Capecitabine + Enzastaurin = 13; Capecitabine + Placebo = 14.

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.

Time frame: Randomization to last visit (up to 9.66 months)

Population: Intent to treat (ITT) population: All randomized participants who received at least 1 dose of study drug with a CR or PR. Participants censored: Capecitabine + Enzastaurin = 3; Capecitabine + Placebo = 2.

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+) .

Time frame: Randomization, Cycle 2, end of study

Population: Zero participants were analyzed. The study was terminated and no data was collected.

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.

Time frame: Randomization to date of death from any cause up to 20.83 months

Population: Intent-to-treat (ITT) population: All randomized participants who received at least 1 dose of study drug. Participants censored: Capecitabine + Enzastaurin = 23; Capecitabine + Placebo = 28.

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.

Time frame: Randomization to last visit (up to 9.66 months)

Population: Intent-to-treat (ITT) population: All randomized participants who received at least 1 dose of study drug.

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.

Time frame: Pre-dose to 6 hours post-dose on Day 1 of Cycle 2

Population: All randomized participants who received at least 1 dose of capecitabine and had data for AUC 0-tlast analysis.

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).

Time frame: From pre-dose to 24 hours post-dose on Day 1 of Cycle 2

Population: All randomized participants who received at least 1 dose of enzastaurin and had data for AUCτ,ss analysis.

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.

Time frame: From pre-dose to 6 hours post-dose on Day 1 of Cycle 2

Population: All randomized participants who received at least 1 dose of capecitabine and had data for Cmax analysis.

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.

Time frame: Baseline to study completion [Cycle 19 (21 days/cycle) and 30-day safety follow-up]