Chemotherapy for Participants With Lymphoma

Study Overview
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Brief Summary
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The primary purpose of this study is to help answer the following research questions: To assess whether Enzastaurin combined with rituximab, gemcitabine and oxaliplatin (R-GEMOX) can help participants with Diffuse Large B-Cell Lymphoma (DLBCL) remain free from disease and thus live longer. To assess for any side effects that might be associated with enzastaurin and R-GEMOX . To look at the characteristics and levels of certain genes and proteins to learn more about DLBCL and how enzastaurin works in the body. To look at the level of enzastaurin in the body and how long it remains.

Official Title
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An Open-label, Single Arm, Phase 2 Study of Rituximab, Gemcitabine and Oxaliplatin Plus Enzastaurin as Treatment for Patients With Relapsed Diffuse Large B-Cell Lymphoma

Conditions
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Lymphoma, Large Cell, Diffuse

Intervention / Treatment
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* Drug: enzastaurin
* Drug: gemcitabine
* Drug: rituximab
* Drug: oxaliplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of DLBCL or transformed (cluster differentiation 20 [CD20]+) indolent lymphoma Relapsed/progressed after response obtained in 1st- or 2nd-line treatment, or participants who have not progressed after stable disease (SD) obtained in 1st- or 2nd-line. Measurable disease (lymph node greater than 1.5 cm) Adequate organ function Greater than or equal to 60 years or less than 60 (but greater than or equal to 18 years) who are not eligible for high-dose chemotherapy high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) Exclusion Criteria: Prior Allogeneic transplantation More than 2 prior anticancer treatment regimens Pregnant or breastfeeding Human-immunodeficiency-virus (HIV)associated lymphomas Brain metastases

Ages Eligible for Study
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Minimum Age: 60 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enzastaurin + Gemcitabine Rituximab Oxaliplatin (R-GEMOX)<br> | Drug: enzastaurin<br>* 1125 mg loading dose then 500 mg, oral, daily, until disease progression or 3 years<br>* Other names: LY317615;Drug: gemcitabine<br>* 1000 mg/m², IV, once, every two weeks, four to eight 2 week cycles<br>* Other names: LY188011, Gemzar;Drug: rituximab<br>* 375 mg/m², IV, once every 2 weeks, four to eight 2 week cycles<br>Drug: oxaliplatin<br>* 100 mg/m², IV, once every two weeks, four to eight 2 week cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With Progression Free Survival (PFS) After 1 Year Treatment | 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. | First Dose of Study Drug to Measured Progressive Disease or Death from Any Cause at 1 Year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) - Percentage of Participants Achieving Complete Response (CR) or Complete Response Unconfirmed (CRu) or Partial Response (PR) (Response) | 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. | Baseline to Measured Progressive Disease or Death from Any Cause at End of 4 and 8 Cycles | 
| Percent of Participants With Progression-Free Survival (PFS) After 2 Years and 4 Years of Treatment | 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. | First Dose of Study Drug to Measured Progressive Disease or Death from Any Cause at 2 Years, 4 Years | 
| Percent of Participants With Overall Survival (OS) After 1 Year, 2 Years and 4 Years | 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. | First Dose of Study Drug to Death from Any Cause at 1 Year, 2 Years and 4 Years | 
| Percent of Participants With Event Free Survival (EFS) After 1 Year, 2 Years and 4 Years | 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. | 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 | 
| Progression-Free Survival (PFS ) of Participants With Diffuse Large B-cell Lymphoma (DLBCL) Germinal-Center B-cells (GCB) Versus Non-GCB Molecular Subtypes (Assessment of Biomarkers Relevant for Enzastaurin) | 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. | Baseline, Cycles 1-4, End of Study | 
| PFS of Participants With Diffuse Large B-cell Lymphoma (DLBCL) Protein Kinase C Beta 2 (PKCB2) Expression (Assessment of Biomarkers Relevant for Enzastaurin) | 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. | Baseline, Cycles 1-4, End of Study | 
| Pharmacokinetics (PK): Maximum Observed Drug Concentration During a Dosing Interval at Steady State(Cmax,ss) for Total Analyte [Characterization of Pharmacokinetics of Enzastaurin and Its Metabolites] | 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. | Day 2 of Cycle 2: Predose;1-2 Hours(H);3-4 h;5-6 h;7-8 H Postdose | 
| PK: Area Under the Concentration vs. Time Curve During 1 Dosing Interval at Steady State (AUCτ,ss) for Total Analyte | AUCτ,ss is defined as the area under the concentration versus time curve during 1 dosing interval at steady state. | Day 2 of Cycle 2: Predose;1-2 hours(h);3-4 h;5-6 h;7-8 h Postdose | 
| Percent of Participants With Disease-Free Survival (DFS) at 1 Year, 2 Years and 4 Years | 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. | First Dose of Study Drug to Relapse after CR or CRu or Death from any Cause at 1 Year, 2 Years and 4 Years | 
| Duration of Tumor Response (DOR) | 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 from Observed CR and CRu or PR (Up to 4 Years) |