Chemotherapy for Participants With Lymphoma

PFS is defined as the rate at 1 year from the date of first dose of study drug to the first date of measured PD or death from any cause and was determined using the distribution of overall PFS times. The PFS rate at 1 year was determined using Kaplan-Meier estimates. For participants not known to have died as of the data cut-off date and who do not have PD, PFS was censored at the date of the last progression-free disease assessment.

Time frame: First Dose of Study Drug to Measured Progressive Disease or Death from Any Cause at 1 Year

Population: All randomized participants who received at least 1 dose of study drug. Participants censored =14

Duration of tumor response was defined as the time from the date when the measurement criteria were met for CR and CRu or PR (whichever status was recorded first) until the date of first observation of objective disease progression. For responding patients who died without objective PD (including death from study disease), duration of response was censored at the date of the last objective progression-free disease assessment. For responding patients not known to have died as of the data cut-off date and who do not have objective PD, duration of response was censored at the date of the last objective progression-free disease assessment. For responding patients who received subsequent systemic anticancer therapy (after discontinuation from the study chemotherapy) prior to objectively determined disease progression, duration of response was censored at the date of the last objective progression-free disease assessment prior to post-discontinuation therapy.

Time frame: Time from Observed CR and CRu or PR (Up to 4 Years)

Population: All randomized participants who received at least 1 dose of study drug. Participants censored =13.

Assessment of response was based on the International Workshop to Standardize Response criteria for lymphoma (Cheson et al. 1999). CR is the complete disappearance of all detectable clinical and radiologic evidence of disease; all lymph nodes and nodal masses must have regressed to normal size (≤1.5 cm in their greatest transverse diameter for nodes \>1.5 cm before therapy).CRu is as CR but with 1 or more of the following features: A residual lymph node mass \>1.5 cm in greatest transverse diameter that has regressed by more than 75% in the sum of the products of the greatest diameters (SPD) and/or indeterminate bone marrow with normalization of all biologic abnormalities. PR is regression of more than 50% (SPD) of all measurable lesions, disappearance of nonmeasurable lesions and no new lesion. For each response category the number of participants with this response will be divided by the total number of participants treated to achieve the response rate.

Time frame: Baseline to Measured Progressive Disease or Death from Any Cause at End of 4 and 8 Cycles

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

DFS was calculated as the duration from date of first dose of study drug to the date of first relapse event after CR or CRu or death from any cause. Participants who have not experienced an event at the time of analysis were censored at the most recent date of disease assessment. Events are relapse after a CR or CRu. Related death or death from unknown cause was considered as an event. Unrelated death was not considered as an event and the participant was censored at the time of death for this analysis. Unrelated death was defined as death from a cause not related to the lymphoma, any examination done for the lymphoma, or any treatment of the lymphoma.

Time frame: First Dose of Study Drug to Relapse after CR or CRu or Death from any Cause at 1 Year, 2 Years and 4 Years

Population: All randomized participants who received at least 1 dose of study drug. 7 participants were censored.

Event-free survival time was defined as the time from the date of first dose of study drug to the first date of measured PD,or start of a new treatment for the lymphoma, or death from any cause. For participants not known to have events as of the data cut-off date, EFS was censored at the date of the last tumor assessment.

Time frame: First Dose of Study Drug to Measured PD, or Start of New Lymphoma Treatment or Death from Any Cause at 1 Year, 2 Years and 4 Years

Population: All randomized participants who received at least 1 dose of study drug. 6 participants were censored.

Overall survival was defined as the time from the date of first dose of study drug to the date of death from any cause. For participants who were not still alive at the time of analysis, survival time was censored at the last contact date. For participants not known to have died as of the cut-off date for analysis,OS was censored at the last contact date for participants in post-discontinuation.

Time frame: First Dose of Study Drug to Death from Any Cause at 1 Year, 2 Years and 4 Years

Population: All randomized participants who received at least 1 dose of study drug. 14 participants were censored.

PFS was defined as time from randomization until the first evidence of progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST v1.0) or death from any cause; by Investigator assessment. Progressive disease (PD) was defined as at least a 20% increase in sum of longest diameter of target lesions taking as reference the smallest sum longest diameter since baseline, progression in non-target lesions or the appearance of 1 or more new lesion(s). PFS rate was defined as the rate of PFS at 2 year from the date of first dose of study drug and was determined using the distribution of overall PFS times. PFS rate was defined as the rate of PFS at 4 year from the date of first dose of study drug and was determined using the distribution of overall PFS times. For participants not known to have died as of the data cut-off date and who did not have PD, PFS was censored at the date of the last progression-free disease assessment.

Time frame: First Dose of Study Drug to Measured Progressive Disease or Death from Any Cause at 2 Years, 4 Years

Population: All randomized participants who received at least 1 dose of study drug. 8 participants were censored.

Reported PFS was based on PKCB2 protein expression assessed by immunohistochemistry (scored in 10% increments for percent of tumor cells). Protein expression levels was grouped into high and low in association with the clinical endpoints. Grouping was based on 1) a pre-specified threshold provided by the pathologist at Cleveland Clinic for the diffuse large B-cell lymphoma (DLBCL)-prognostic markers, and 2) a median cut-point for the enzastaurin-specific markers.

Time frame: Baseline, Cycles 1-4, End of Study

Population: All randomized participants who received at least 1 dose of study drug and had evaluable samples.

Cmax,ss is defined as the maximum observed drug concentration during a dosing interval at steady state. Non-Compartmental Pharmacokinetic Parameters for Total Analyte (Enzastaurin + LSN326020). LSN326020 is Enzastaurin's major active metabolite.

Time frame: Day 2 of Cycle 2: Predose;1-2 Hours(H);3-4 h;5-6 h;7-8 H Postdose

Population: All randomized participants who received at least 1 dose of study drug and evaluable PK data.

AUCτ,ss is defined as the area under the concentration versus time curve during 1 dosing interval at steady state.

Time frame: Day 2 of Cycle 2: Predose;1-2 hours(h);3-4 h;5-6 h;7-8 h Postdose

Population: All randomized subjects who received at least 1 dose of study drug and evaluable PK data.

PFS based on DLBCL molecular subtypes (GCB vs non-GCB) were determined. The molecular characterization of germinal center B-cells (GCBs) vs. non-GCBs was analyzed as separate combination immunohistochemistry (IHC) markers based on the Hans algorithms. Molecular subtype was included as class effect in the analytical models, adjusting for International Prognostic Index (IPI) score.

Time frame: Baseline, Cycles 1-4, End of Study

Population: All randomized participants who received at least 1 dose of study drug and had evaluable samples.