A Study of Participants With Lymphoma Who Take R-CHOP and Enzastaurin Compared to Participants Who Take R-CHOP Only

Study Overview
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Brief Summary
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To compare R-CHOP plus enzastaurin versus R-CHOP for progression-free survival (PFS) time measured in participants with intermediate and/or high risk for diffuse large B-cell lymphoma (DLBCL) receiving first-line treatment.

Official Title
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An Open-label, Randomized, Phase 2 Study of R-CHOP Plus Enzastaurin Versus R-CHOP in the First-Line Treatment of Patients With Intermediate and High-Risk Diffuse Large B-Cell Lymphoma

Conditions
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Lymphoma

Intervention / Treatment
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* Drug: enzastaurin
* Drug: rituximab
* Drug: cyclophosphamide
* Drug: doxorubicin
* Drug: vincristine
* Drug: prednisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must: Have a histologically confirmed diagnosis of DLBCL based on the World Health Organization classification (Harris et al. 1999) at the time of original diagnosis. Pathology must be reviewed and confirmed prior to enrollment at the investigational site where the participant is entered. Participants with a prior history of an indolent lymphoma or a histological diagnosis of follicular Grade 3 lymphoma will not be eligible for enrollment. Have received no prior chemotherapy. Have an International Prognostic Index (IPI) score ≥2 at time of original diagnosis. Have a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology group (ECOG) scale. Have adequate organ function as follows: Hepatic: total bilirubin ≤1.5 times the upper limit of normal (x ULN); alanine transaminase (ALT) and aspartate transaminase (AST) ≤1.5 x ULN, (≤5 x ULN, if liver involvement). Renal: serum creatinine ≤1.5 x ULN. Adequate bone marrow reserve: platelets ≥75 x 10^9 per Liter (L), absolute neutrophil count (ANC) ≥1.0 x 10^9 per L, unless there is bone marrow involvement. Exclusion Criteria: Participants must not: Have received treatment within the last 30 days with a drug (not including enzastaurin) that has not received regulatory approval for any indication at the time of study entry. Are receiving concurrent administration of any other systemic anticancer therapy. Are pregnant or breastfeeding. Are unable to swallow tablets. Are unable to discontinue use of carbamazepine, phenobarbital, and phenytoin at least 14 days prior to study enrollment.

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: R-CHOP and Enzastaurin<br>R-CHOP includes rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone treatment therapies. | Drug: enzastaurin<br>* 1125 milligrams (mg) then 500 mg, oral, daily, six 21-day cycles or up to 3 years<br>* Other names: LY317615;Drug: rituximab<br>* 375 milligrams per square meter (mg/m^2), intravenous (IV), Day 1 every 21 days, six 21-day cycles<br>Drug: cyclophosphamide<br>* 750 mg/m^2, IV, Day 1 every 21 days, six 21-day cycles<br>Drug: doxorubicin<br>* 50 mg/m^2, IV, Day 1 every 21 days, six 21-day cycles<br>Drug: vincristine<br>* 1.4 mg/m^2, IV, Day 1 every 21 days, six 21-day cycles<br>Drug: prednisone<br>* 100 mg, oral, Days 1-5, six 21-day cycles<br>|
| Active Comparator: R-CHOP<br>R-CHOP includes rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone treatment therapies. | Drug: rituximab<br>* 375 milligrams per square meter (mg/m^2), intravenous (IV), Day 1 every 21 days, six 21-day cycles<br>Drug: cyclophosphamide<br>* 750 mg/m^2, IV, Day 1 every 21 days, six 21-day cycles<br>Drug: doxorubicin<br>* 50 mg/m^2, IV, Day 1 every 21 days, six 21-day cycles<br>Drug: vincristine<br>* 1.4 mg/m^2, IV, Day 1 every 21 days, six 21-day cycles<br>Drug: prednisone<br>* 100 mg, oral, Days 1-5, six 21-day cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) Time | PFS time is the elapsed time from the date of randomization to the first date of objectively-determined PD or death from any cause. PD was assessed according to International Working Group recommendations (Cheson et al. 1999). PD: Enlarging liver/spleen nodules, new or increased lymph nodes/masses and reappearance of bone marrow infiltrate. For participants not known to have died as of the data cut-off date and who did not have objective PD, PFS was censored at the date of the last objective progression-free disease assessment. For participants who received subsequent anticancer therapy (other than enzastaurin maintenance therapy) prior to objectively determined disease progression or death, PFS was censored at the date of the last objective progression-free disease assessment prior to the date of subsequent therapy. | Randomization to measured PD or death from any cause (up to 55 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response (CR and CRu) and Objective Response [CR, CRu, and Partial Response (PR)] (Overall Response Rate) | CR, CRu, and PR were defined using International Working Group recommendations (Cheson et al. 1999). CR is a complete disappearance of all disease with the exception of nodes. No new lesions. Previously enlarged organs must have regressed and not be palpable. Bone marrow must be negative if positive at baseline. Normalization of markers. CRu does not qualify for CR above, due to a residual nodal mass or an indeterminate bone marrow. PR is a 50% decrease in the sum of the products of diameters for up to 6 identified dominant lesions, including splenic and hepatic nodules from baseline. No new lesions and no increase in the size of liver, spleen or other nodes. The percentage of participants with complete response (CR/CRu) and objective response (Cr/CRu/PR)=(Number of participants whose best overall response was CR/CRu or Cr/CRu/PR)/(Number of participants treated)*100. | Baseline through long-term follow-up (up to 2 years post last dose) | 
| Percentage of Participants Alive Progression-Free at Year 2 (2-Year PFS Rate) | PD was assessed according to International Working Group recommendations (Cheson et al. 1999). PD: Enlarging liver/spleen nodules, new or increased lymph nodes/masses and reappearance of bone marrow infiltrate. Percentage of participants alive progression-free at Year 2=(Number of participants alive progression free at Year 2)/(Number of participants assessed)*100. | Randomization to measured PD (up to Year 2) | 
| Percentage of Participants With a PET-Negative Scan (PET-Negative Rate) | The percentage of participants with a PET-negative scan=(Number of participants who had a PET-negative scan at Cycle 6)/(Number of participants who had a PET-positive scan at baseline)*100. | Cycle 6 (21 days/cycle) | 
| Percentage of Participants With Complete Response (CR/CRu) and/or Post-Baseline PET-Negative Scan (Concordance Between Response and PET Scan) | Lesion response was assessed according to International Working Group recommendations (Cheson et al. 1999). CR is a complete disappearance of all disease with the exception of nodes. No new lesions. Previously enlarged organs must have regressed and not be palpable. Bone marrow must be negative if positive at baseline. Normalization of markers. CRu does not qualify for CR above, due to a residual nodal mass or an indeterminate bone marrow. Percentage of participants with CR/CRu and/or PET-negative scan=(Number of participants with complete response and/or PET-negative scan at Cycle 6)/(Number of participants with a PET-positive scan at baseline)*100. | Cycle 6 (21 days/cycle) | 
| Event-Free Survival (EFS) | EFS is the elapsed time from the date of randomization to the first date of objectively-determined PD, institution of a new anticancer treatment (other than maintenance therapy), or death from any cause. PD was assessed according to International Working Group recommendations (Cheson et al. 1999). PD: Enlarging liver/spleen nodules, new or increased lymph nodes/masses and reappearance of bone marrow infiltrate. For participants not known to have died as of the data cut-off date, who did not have objectively determined disease progression, and who were not treated with a new anticancer treatment, EFS was censored at the date of the last objectively determined disease-free assessment. | Randomization to measured PD, start of new therapy, or death from any cause (up to 55 months) | 
| Overall Survival (OS) | OS is the elapsed time from the date of study enrollment (baseline) to the date of death from any cause. For participants not known to have died as of the data cutoff date, OS was censored at the last contact date or last date known to be alive, whichever was later. | Baseline to death from any cause (up to 55 months) | 
| Duration of Complete Response (CR or CRu) | Duration of response (DOR) either CR or CRu: Elapsed time from date CR or CRu criteria met to first objectively-determined PD. For responding participants (pts) who died without PD and pts not known to have died as of data cut-off date, who did not have PD, DOR censored at date of last objective progression-free disease assessment. For responding pts who received subsequent systemic anticancer therapy (other than enzastaurin maintenance therapy) prior to PD, DOR was censored at date of last objective progression-free disease assessment prior to subsequent therapy. CR and CRu defined using International Working Group recommendations (Cheson et al. 1999). CR is a complete disappearance of all disease with the exception of nodes. No new lesions. Previously enlarged organs must have regressed and not be palpable. Bone marrow (BM) must be negative if positive at baseline. Normalization of markers. CRu does not qualify for CR above, due to a residual nodal mass or an indeterminate BM. | Time of response to PD (up to 55 months) | 
| Participants Who Had Treatment-Emergent Adverse Events (TEAEs) or Died (Evaluate Toxicity and Tolerability of R-CHOP Plus Enzastaurin) | Data presented are the number of participants who experienced at least 1 TEAE, Grade 3 or 4 Common Terminology Criteria for Adverse Events (CTCAE), serious adverse event (SAE), as well as the number of participants who discontinued due to an adverse event (AE) or SAE, who died on therapy, died within 30 days post treatment or within 60 days of first dose. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. | First dose through 30 days post study treatment discontinuation (up to 56 months) | 
| PFS of Participants With High or Low Expression of Protein Biomarkers and Correlation of Biomarkers to PFS | Reported is PFS of participants (pts) with high or low biomarker expression levels. PFS: time from randomization to first date of PD/death from any cause. PD assessed according to International Working Group recommendations (Cheson et al. 1999). PD: Enlarging liver/spleen nodules, new/increased lymph node/masses and reappearance of bone marrow infiltrate. For pts who had subsequent anticancer therapy, PFS censored at date of last assessment prior to subsequent therapy. Biomarkers and number of pts censored: EIF4EBP1 Cytoplasm (C) 4,3,7,3; EIF4EBP1 Nucleus (N) 0,2,11,4; EIF4E C 5,2,6,4; EIF4E N 0,0,11,6; HDAC2 N 5,1,5,5; PCREB N 5,3,6,4; PEIF3746 C 4,2,7,4; PEIF3746 N 5,2,6,4; PEIFS209 C 5,2,5,4; PEIFS65 N 7,2,4,4; PEIFT70 C 5,2,6,4; PEIFT70 N 6,4,5,2; P GSK3B C 7,3,4,3; PKCb2 C 4,3,7,3; PS6 C 9,4,1,1; PTEN C 5,2,6,4; PTEN N 3,0,8,6. Correlation of biomarkers with PFS (statistical analyses) reported if high expression groups combined and low expression groups combined each had ≥10 pts. | Randomization to measured PD or death from any cause (up to 55 months)] |